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Wang N, Pan D, Wang X, Su M, Wang X, Yan Q, Sun G, Wang S. NAPRT, but Not NAMPT, Provides Additional Support for NAD Synthesis in Esophageal Precancerous Lesions. Nutrients 2022; 14:4916. [PMID: 36432602 PMCID: PMC9695206 DOI: 10.3390/nu14224916] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
It is hypothesized that esophageal precancerous lesions (EPLs) have a surge requirement for coenzyme I (NAD). The purpose of this study is to clarify the key control points of NAD synthesis in developing EPL by detecting related markers and the gene polymorphism of NAD synthesis and metabolism. This case-control study was conducted in Huai'an, China. In total, 100 healthy controls and 100 EPL cases matched by villages, gender, and age (±2 years) were included. The levels of plasma niacin and nicotinamide, and the protein concentration of NAMPT, NAPRT, and PARP-1 were quantitatively analyzed. PARP-1 gene polymorphism was detected to determine if the cases differed genetically in NAD synthesis. The levels of plasma niacin and nicotinamide and the concentrations of NAMPT were not related to the risk of EPL, but the over-expressions of NAPRT (p = 0.014, 0.001, and 0.016, respectively) and PARP-1 (p for trend = 0.021) were associated with the increased EPL risk. The frequency distribution of APRP-1 genotypes was found to not differ between the two groups, while the EPL group showed an increased frequency of the variant C allele. NAPRT, but not NAMPT, was found to be responsible for the stress of excess NAD synthesis in EPL. Focusing on the development of NAPRT inhibitors may be beneficial to prevent and control ESCC.
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Affiliation(s)
- Niannian Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China
| | - Da Pan
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China
| | - Xuemei Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China
| | - Ming Su
- Huai’an District Center for Disease Control and Prevention, Huai’an 223001, China
| | - Xin Wang
- Huai’an District Center for Disease Control and Prevention, Huai’an 223001, China
| | - Qingyang Yan
- Huai’an District Center for Disease Control and Prevention, Huai’an 223001, China
| | - Guiju Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China
| | - Shaokang Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China
- Department of Public Health, School of Medicine, Xizang Minzu University, Xianyang 712000, China
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Thakur N, Yim K, Abdul-Ghafar J, Seo KJ, Chong Y. High Poly(ADP-Ribose) Polymerase Expression Does Relate to Poor Survival in Solid Cancers: A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:5594. [PMID: 34830749 PMCID: PMC8615806 DOI: 10.3390/cancers13225594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 12/20/2022] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) is a DNA damage repair protein, and its inhibitors have shown promising results in clinical trials. The prognostic significance of PARP is inconsistent in studies of various cancers. In the present study, we conducted a systematic review and meta-analysis to reveal the prognostic and clinicopathological significance of PARP expression in multiple solid cancers. We searched the MEDLINE, EMBASE, and Cochrane databases for relevant research articles published from 2005 to 2021. The pooled hazard ratio (HR) with confidence interval (CI) was calculated to investigate the relationship between PARP expression and survival in multiple solid cancers. In total, 10,667 patients from 31 studies were included. A significant association was found between higher PARP expression and overall survival (OS) (HR = 1.54, 95% CI = 1.34-1.76, p < 0.001), disease-free survival (DFS) (HR = 1.15, 95% CI = 1.10-1.21, p < 0.001), and progression-free survival (PFS) (HR = 1.05, 95% CI = 1.03-1.08, p < 0.001). Subgroup analyses showed that PARP overexpression was significantly related to poor OS in patients with breast cancers (HR = 1.38, 95% CI = 1.28-1.49, p < 0.001), ovary cancers (HR = 1.21, 95% CI = 1.10-1.33, p = 0.001), lung cancers (HR = 2.11, 95% CI = 1.29-3.45, p = 0.003), and liver cancers (HR = 3.29, 95% CI = 1.94-5.58, p < 0.001). Regarding ethnicity, Asian people have almost twice their worst survival rate compared to Caucasians. The pooled odds ratio analysis showed a significant relationship between higher PARP expression and larger tumour size, poor tumour differentiation, lymph node metastasis, distant metastasis, higher TNM stage and lymphovascular invasion, and positive immunoreactivity for Ki-67, BRCA1, and BRCA2. In addition, nuclear expression assessed by the QS system using Abcam and Santa Cruz Biotechnology seems to be the most commonly used and reproducible IHC method for assessing PARP expression. This meta-analysis revealed that higher PARP expression was associated with a worse OS, DFS, and PFS in patients with solid cancers. Moreover, inhibition of this pathway through its specific inhibitors may extend the survival of patients with higher PARP expression.
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Affiliation(s)
| | | | | | | | - Yosep Chong
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 07345, Korea; (N.T.); (K.Y.); (J.A.-G.); (K.J.S.)
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Wang Y, Xia XB, Tang HZ, Cai JR, Shi XK, Ji HX, Yan XN, Xu T. Association of T2285C polymorphism in PARP1 gene coding region with its expression, activity and NSCLC risk along with prognosis. Mutagenesis 2021; 36:281-293. [PMID: 34132814 DOI: 10.1093/mutage/geab022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/15/2021] [Indexed: 11/12/2022] Open
Abstract
Poly (ADP-ribose) polymerase-1(PARP1), a DNA repair gene, is the crucial player in the maintenance of genome integrity. T2285C polymorphism in coding region of PARP1 has been reported to be associated with susceptibility to tumors. We explored the relation and mechanism of T2285C polymorphism of PARP1 to its expression and activity along with risk and prognosis in NSCLC. mRNA expression was measured using qRT-PCR assay or collected from TCGA dataset. Protein expression was examined with immunoblotting assay. Genotypes were determined by PCR-RFLP and sequencing approaches. PARP1 activity was determined with enzyme activity assay. Regulation of SIRT7 to PARP1 were determined by over-expression and small interference experiment. Association of PARP1 T2285C polymorphism with NSCLC risk was evaluated via multiple logistic regression analysis. Comparison of treatment response and PFS of NSCLC patients among different genotypes or regimens was made by Chi-square test. Results indicated that mRNA and protein expression of PARP1 dramatically increased in NSCLC tissues in comparison to paired para-carcinoma tissues (P<0.05). TC/CC mutant genotypes were associated with markedly enhanced PARP1 mRNA level compared with TT genotype (P=0.011). No significant difference was discovered in PARP1 protein expression among TT, TC or CC genotypes (P>0.05). Subjects with variant allele C had higher risk of NSCLC in comparison to allele T carriers [odds ratio (OR) =1.560; P=0.000]. NSCLC patients carrying mutational TC or CC genotypes were correlated with unfavorable response to platinum-based chemotherapy (TT vs.TC vs.CC, P=0.010), and shorter PFS compared to TT genotype (TT vs.TC vs.CC, P=0.009). T2285C mutation of PARP1 resulted in the enhancement of its mRNA, but the decrease of enzyme activity in tumor cell. Overexpression of SIRT7 attenuated PARP1 expression and activity. These findings suggest the variant allele C of T2285C polymorphism of PARP1 linked to an increase of NSCLC risk, and unfavorable efficacy and prognosis of NSCLC patients with platinum-based chemotherapy, which might be associated with enhancement of its mRNA expression and the diminishment of activity. Identification of PARP1 T2285C polymorphism and mRNA expression may be the promising way for the individualized treatment of NSCLC.
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Affiliation(s)
- Yan Wang
- Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiao Bing Xia
- Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hui Zhuo Tang
- Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jing Ran Cai
- Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiang Kui Shi
- Department of Pharmacy, the Affiliated Xuzhou Maternity and Child Health Care Hospital of Xuzhou Medical University, Xuzhou, China
| | - Huai Xue Ji
- Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiao Nan Yan
- Clinical Center of Reproductive Medicine, Xuzhou Central Hospital, Xuzhou, China
| | - Tie Xu
- Emergency Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
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Xin Y, Yang L, Su M, Cheng X, Zhu L, Liu J. PARP1 rs1136410 Val762Ala contributes to an increased risk of overall cancer in the East Asian population: a meta-analysis. J Int Med Res 2021; 49:300060521992956. [PMID: 33706586 PMCID: PMC8168028 DOI: 10.1177/0300060521992956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objectives To investigate the association between poly(ADP-ribose) polymerase 1 (PARP1) rs1136410 Val762Ala and cancer risk in Asian populations, as published findings remain controversial. Methods The PubMed and EMBASE databases were searched, and references of identified studies and reviews were screened, to find relevant studies. Meta-analyses were performed to evaluate the association between PARP1 rs1136410 Val762Ala and cancer risk, reported as odds ratio (OR) and 95% confidence interval (CI). Results A total of 24 studies with 8 926 cases and 15 295 controls were included. Overall, a significant association was found between PARP1 rs1136410 Val762Ala and cancer risk in East Asians (homozygous: OR 1.19, 95% CI 1.06, 1.35; heterozygous: OR 1.10, 95% CI 1.04, 1.17; recessive: OR 1.13, 95% CI 1.02, 1.25; dominant: OR 1.13, 95% CI 1.06, 1.19; and allele comparison: OR 1.09, 95% CI 1.03, 1.15). Stratification analyses by race and cancer type revealed similar results for gastric cancer among the Chinese population. Conclusion The findings suggest that PARP1 rs1136410 Val762Ala may be significantly associated with an increased cancer risk in Asians, particularly the Chinese population.
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Affiliation(s)
- Yijuan Xin
- Department of Clinical Laboratory, 66352Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China
| | - Liu Yang
- Department of Clinical Laboratory, 66352Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China
| | - Mingquan Su
- Department of Clinical Laboratory, 66352Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China
| | - Xiaoli Cheng
- Department of Clinical Laboratory, 66352Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China
| | - Lin Zhu
- Department of Clinical Laboratory, 66352Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China
| | - Jiayun Liu
- Department of Clinical Laboratory, 66352Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China
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Saitoh T, Oda T. DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment. Cancers (Basel) 2021; 13:504. [PMID: 33525741 PMCID: PMC7865954 DOI: 10.3390/cancers13030504] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/21/2021] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.
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Affiliation(s)
- Takayuki Saitoh
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Tsukasa Oda
- Laboratory of Molecular Genetics, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan;
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Li H, Zha Y, Du F, Liu J, Li X, Zhao X. Contributions of PARP-1 rs1136410 C>T polymorphism to the development of cancer. J Cell Mol Med 2020; 24:14639-14644. [PMID: 33108038 PMCID: PMC7753995 DOI: 10.1111/jcmm.16027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 09/24/2020] [Accepted: 10/07/2020] [Indexed: 12/13/2022] Open
Abstract
Poly(ADP‐ribose) polymerase‐1 (PARP‐1) is a nuclear chromatin‐associated enzyme involved in the DNA damage response. SNP rs1136410 C>T, the most studied polymorphism in PARP‐1 gene, is highly implicated in the susceptibility of cancer. However, the roles of PARP‐1 rs1136410 C>T on cancer risk vary from different studies. We comprehensively screened all qualified publications from several databases, including PubMed, EMBASE, MEDLINE, CNKI and Wanfang. The searching was updated to April 2020. Our meta‐analysis included 60 articles with 65 studies, comprised of a total of 23 996 cases with cancer and 33 015 controls. Overall, pooled data showed that the PARP‐1 rs1136410 C>T polymorphism was significantly but a border‐line associated with an increased risk of overall cancer (CC vs. TT/TC: OR = 1.11, 95% CI = 1.00‐1.24; C vs T: OR = 1.07, 95% CI = 1.01‐1.14). Subgroup analysis indicated that rs1136410 C allele contributed to high risk among gastric, thyroid, and cervical cancer, but lower risk among brain cancer. Furthermore, increased cancer risk was detected in the subgroups of Asian, controls from population‐based design studies, and HWE ≤ 0.05 studies. Sensitivity analysis and Egger's test showed that results of the meta‐analysis were fairly stable. The current study indicated that PARP1 rs1136410 C>T polymorphism may have an impact on certain types of cancer susceptibility.
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Affiliation(s)
- Hunian Li
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yongjiu Zha
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Fang Du
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Jie Liu
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiaoquan Li
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Xu Zhao
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
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Polymorphisms in PARP1 predict disease-free survival of triple-negative breast cancer patients treated with anthracycline/taxane based adjuvant chemotherapy. Sci Rep 2020; 10:7349. [PMID: 32355298 PMCID: PMC7192942 DOI: 10.1038/s41598-020-64473-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 04/15/2020] [Indexed: 01/15/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive disease and of poor prognosis. It is very important to identify novel biomarkers to predict therapeutic response and outcome of TNBC. We investigated the association between polymorphisms in PARP1 gene and clinicopathological characteristics or survival of 272 patients with stage I-III primary TNBC treated with anthracycline/taxane based adjuvant chemotherapy. We found that after adjusted by age, grade, tumor size, lymph node status and vascular invasion, rs7531668 TA genotype carriers had significantly better DFS rate than TT genotype carriers, the 5 y DFS was 79.3% and 69.2% (P = 0.046, HR 0.526 95% CI 0.280-0.990). In lymph node negative subgroup, DFS of rs6664761 CC genotype carriers was much better than TT genotype carriers (P = 0.016, HR 0.261 95% CI 0.088-0.778) and DFS of rs7531668 AA genotype carriers was shorter than TT genotype carriers (P = 0.015, HR 3.361 95% CI 1.259-8.969). In subgroup of age ≤ 50, rs6664761 TC genotype predicted favorable DFS than TT genotype (P = 0.042, HR 0.405 95% CI 0.170-0.967). Polymorphisms in PARP1 gene had no influence on treatment toxicities. After multivariate analysis, tumor size (P = 0.037, HR = 2.829, 95% CI: 1.063-7.525) and lymph node status (P < 0.001, HR = 9.943, 95% CI: 2.974-33.243) were demonstrated to be independent prognostic factors. Our results suggested that polymorphisms in PARP1 gene might predict the DFS of TNBC patients treated with anthracycline/taxane based adjuvant chemotherapy.
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Gotoh N, Minato Y, Saitoh T, Takahashi N, Kasamatsu T, Souma K, Oda T, Hoshino T, Sakura T, Ishizaki T, Shimizu H, Takizawa M, Yokohama A, Tsukamoto N, Handa H, Murakami H. PARP1 V762A polymorphism affects the prognosis of myelodysplastic syndromes. Eur J Haematol 2020; 104:526-537. [PMID: 32003046 DOI: 10.1111/ejh.13393] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/26/2020] [Accepted: 01/28/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Myelodysplastic syndromes (MDS), caused by various genetic mutations in hematopoietic stem cells, are associated with highly variable outcomes. Poly (ADP-ribose) polymerase-1 (PARP1) plays an important role in DNA damage repair and contributes to the progression of several types of cancer. Here, we investigated the impact of PARP1 V762A polymorphism on the susceptibility to and prognosis of MDS. METHODS Samples collected from 105 MDS patients and 202 race-matched healthy controls were subjected to polymerase chain reaction-restriction fragment length polymorphism for genotyping. RESULTS The allele and genotype frequencies of PARP1 V762A did not differ between MDS patients and the control group. However, MDS patients with the PARP1 V762A non-AA genotype, which is associated with high gene activity, had shorter overall survival rates (P = .01) than those with the AA genotype. Multivariate analysis of overall survival also revealed PARP1 V762A non-AA genotype as a poor prognostic factor (P = .02). When patients were analyzed according to treatment history, the PARP1 V762A non-AA genotype was only associated with poor survival in patients who had received treatment (P = .02). CONCLUSION PARP1 V762A polymorphism may be an independent prognostic factor for MDS, and a predictive biomarker for MDS treatment.
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Affiliation(s)
- Nanami Gotoh
- Graduate School of Health Sciences, Gunma University, Gunma, Japan
| | - Yusuke Minato
- Department of Virology and Preventive Medicine, Gunma University Graduate School of Medicine, Gunma, Japan.,Department of Anatomy and Cell Biology, Hyogo College of Medicine, Hyogo, Japan
| | - Takayuki Saitoh
- Graduate School of Health Sciences, Gunma University, Gunma, Japan
| | | | | | - Kana Souma
- Graduate School of Health Sciences, Gunma University, Gunma, Japan
| | - Tsukasa Oda
- Laboratory of Molecular Genetics, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | - Takumi Hoshino
- Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan
| | - Toru Sakura
- Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan
| | - Takuma Ishizaki
- Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Hiroaki Shimizu
- Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Makiko Takizawa
- Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Akihiko Yokohama
- Division of Blood Transfusion Service, Gunma University Hospital, Gunma, Japan
| | | | - Hiroshi Handa
- Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan
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Khan AU, Mahjabeen I, Malik MA, Hussain MZ, Khan S, Kayani MA. Modulation of brain tumor risk by genetic SNPs in PARP1gene: Hospital based case control study. PLoS One 2019; 14:e0223882. [PMID: 31609976 PMCID: PMC6791555 DOI: 10.1371/journal.pone.0223882] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/01/2019] [Indexed: 12/21/2022] Open
Abstract
PARP-1 gene plays an essential part in base excision repair pathway and its functional variations result in several types of cancer. In this study we have explored the effect of genetic variations in PARP-1 gene in brain tumorigenesis. This case control study comprised of 500 brain tumor cases along with 500 healthy controls. Three polymorphisms of PARP-1 gene, rs1136410 (Val762Ala), rs1805404 (Asp81Asp) and rs1805414 (Ala284Ala) were analyzed using AS-PCR method followed by DNA sequencing. Joint effect model, haplotype analysis and linkage disequilibrium of these polymorphisms was assessed using Haploview 4.2. In rs1136410 (Val762Ala) heterozygous mutant genotype (CT) was observed notably lower (OR: 0.44., 95% CI: 0.33-0.57., p<0.0001) in brain tumor patients compared to controls and ~2 fold increased frequency of homozygous mutant genotype (CC) was observed in brain tumor patients versus controls (OR: 1.51., 95%CI: 1.16-1.96, p = 0.001). In rs1805414 (Ala284Ala), frequency of heterozygous mutant genotype (CT) was observed lower (OR: 0.77., 95% CI: 0.60-0.99., p = 0.05) in patients versus controls. In rs1805404 (Asp81Asp), heterozygous mutant genotyping (CT) was observed lower in brain tumor patients compared with the healthy controls (OR: 0.63., 95% CI: 0.48-0.83., p = 0.001). However, homozygous mutant genotype (TT) was observed increased in patients compared to controls (OR: 1.41., 95% CI:1.07-1.85., p = 0.01). We assessed the fact that in combination the PARP-1 gene SNPs, rs1136410 (Val762Ala), rs1805414 (Ala284Ala) and rs1805404 (Asp81Asp) may increase the brain pathogenesis at least in Pakistani population.
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Affiliation(s)
- Asad ullah Khan
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | | | - Muhammad Zahid Hussain
- Department of Medicine, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
| | - Sarfraz Khan
- Department of Physiotherapy, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
- * E-mail:
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Sharma N, Saxena S, Agrawal I, Singh S, Srinivasan V, Arvind S, Epari S, Paul S, Jha S. Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma. Sci Rep 2019; 9:8480. [PMID: 31186453 PMCID: PMC6559951 DOI: 10.1038/s41598-019-44854-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 05/22/2019] [Indexed: 02/07/2023] Open
Abstract
Gliomas are the most prevalent primary brain tumors with immense clinical heterogeneity, poor prognosis and survival. The nucleotide-binding domain, and leucine-rich repeat containing receptors (NLRs) and absent-in-melanoma 2 (AIM2) are innate immune receptors crucial for initiation and progression of several cancers. There is a dearth of reports linking NLRs and AIM2 to glioma pathology. NLRs are expressed by cells of innate immunity, including monocytes, macrophages, dendritic cells, endothelial cells, and neutrophils, as well as cells of the adaptive immune system. NLRs are critical regulators of major inflammation, cell death, immune and cancer-associated pathways. We used a data-driven approach to identify NLRs, AIM2 and NLR-associated gene expression and methylation patterns in low grade glioma and glioblastoma, using The Cancer Genome Atlas (TCGA) patient datasets. Since TCGA data is obtained from tumor tissue, comprising of multiple cell populations including glioma cells, endothelial cells and tumor-associated microglia/macrophages we have used multiple cell lines and human brain tissues to identify cell-specific effects. TCGA data mining showed significant differential NLR regulation and strong correlation with survival in different grades of glioma. We report differential expression and methylation of NLRs in glioma, followed by NLRP12 identification as a candidate prognostic marker for glioma progression. We found that Nlrp12 deficient microglia show increased colony formation while Nlrp12 deficient glioma cells show decreased cellular proliferation. Immunohistochemistry of human glioma tissue shows increased NLRP12 expression. Interestingly, microglia show reduced migration towards Nlrp12 deficient glioma cells.
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Affiliation(s)
- Nidhi Sharma
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - Shivanjali Saxena
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - Ishan Agrawal
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - Shalini Singh
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - Varsha Srinivasan
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - S Arvind
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - Sridhar Epari
- Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Sushmita Paul
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India
| | - Sushmita Jha
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India.
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Bashir K, Sarwar R, Saeed S, Mahjabeen I, Kayani MA. Interaction among susceptibility genotypes of PARP1 SNPs in thyroid carcinoma. PLoS One 2018; 13:e0199007. [PMID: 30183716 PMCID: PMC6124699 DOI: 10.1371/journal.pone.0199007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 04/16/2018] [Indexed: 01/21/2023] Open
Abstract
Polymorphisms in DNA repair genes may alter the repair mechanism which makes the person susceptible to DNA damage. Polymorphic variants in these DNA repair pathway genes such as Poly (ADP-ribose) polymerase- 1 (PARP1) have been associated with susceptibility of several types of cancer including thyroid. Many studies have been published on PARP1 gene polymorphisms and carcinogenesis with inconsistent results. The present study was designed to explore the link between the PARP1 polymorphisms and thyroid cancer risk. This case-control study was comprised of 456 thyroid cancer patients and 400 healthy controls. Three SNPs of PARP1 gene; rs1136410, rs1805414 and rs1805404 were analyzed using ARMS-PCR. The combined genotype and haplotype analysis were performed using haploview software 4.2. Major allele homozygote (CC) of rs1136410 and combined genotype (TT+TC) of rs180414 showed a significant association with thyroid cancer risk (OR = 1.30; 95% CI 0.99–1.77; P = 0.05) and (OR = 0.43; 95% CI = 0.27–0.67; P = 0.03). Histological subtype analysis showed the significant association of selected PARP1 SNPs with papillary, follicular and anaplastic subtypes in thyroid cancer patients. Haplotype analysis showed that TCT (p = 0.01), CTT (p = 0.02) and CTC (p = 0.03) were significantly higher in controls when compared to cases. However, TTC (p = 0.05) and TCC (p = 0.01) haplotype frequency was significantly higher in cases compared to controls. Global haplotype analysis showed that there was an overall significant difference between cases and controls (p = 0.001). Identification of these genetic risk markers may provide evidence for exploring insight into mechanisms of pathogenesis and subsequently aid in developing novel therapeutic strategies for thyroid cancer.
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Affiliation(s)
- Kashif Bashir
- Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan
| | - Romana Sarwar
- Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan
| | - Soma Saeed
- Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan
- * E-mail:
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12
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De Mello RA, Castelo-Branco L, Castelo-Branco P, Pozza DH, Vermeulen L, Palacio S, Salzberg M, Lockhart AC. What Will We Expect From Novel Therapies to Esophageal and Gastric Malignancies? Am Soc Clin Oncol Educ Book 2018; 38:249-261. [PMID: 30231398 DOI: 10.1200/edbk_198805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Esophageal cancer and gastric cancer are aggressive diseases for which treatment approaches are facing a new era. Some molecular pathways, such as VEGF, EGFR, fibroblast growth factor receptor, PIK3CA, and PARP-1, have been studied, and novel targeted drugs are presumed to be developed in the near future. From The Cancer Genome Atlas report, 80% of Epstein-Barr virus tumors and 42% of tumors with microsatellite instability have PIK3CA mutations, suggesting that this pathway could be reevaluated as a possible target for new systemic treatment of gastric cancer. Notably, higher PARP-1 expression can be found in gastric cancer, which might be related to more advanced disease and worse prognosis. In addition, PD-L1 expression, high microsatellite instability, and mismatch repair deficiency can be found in gastric cancer, thus suggesting that immunotherapy may also play a role in those patients. We discuss trends related to the potential of novel therapies for patients with esophageal and gastric cancers in the near future.
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Affiliation(s)
- Ramon Andrade De Mello
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Luis Castelo-Branco
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Pedro Castelo-Branco
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Daniel Humberto Pozza
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Louis Vermeulen
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Sofia Palacio
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Matthew Salzberg
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - A Craig Lockhart
- From the Department of Biomedical Sciences and Medicine, Division of Oncology, University of Algarve, Faro, Portugal; Algarve Biomedical Center, Campus Gambelas, Faro, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; Research Centre, Division of Medical Oncology, Hospital São Mateus, NOHC Clinic, Fortaleza, CE, Brazil; Algarve Hospital and University Center, Department of Oncology, Faro, Portugal; Portuguese Public Health School, Nova University, Lisbon, Portugal; Centre for Biomedical Research, University of Algarve, Faro, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal; Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, The Netherlands; and the Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
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13
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Azevedo AP, Silva SN, De Lima JP, Reichert A, Lima F, Júnior E, Rueff J. DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms. Oncol Lett 2017; 13:4641-4650. [PMID: 28599464 PMCID: PMC5452988 DOI: 10.3892/ol.2017.6065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 01/26/2017] [Indexed: 02/06/2023] Open
Abstract
The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog (E. coli) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility.
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Affiliation(s)
- Ana P Azevedo
- Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculty of Medical Sciences, NOVA University of Lisbon, 1169-056 Lisbon, Portugal.,Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449-005 Lisbon, Portugal
| | - Susana N Silva
- Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculty of Medical Sciences, NOVA University of Lisbon, 1169-056 Lisbon, Portugal
| | - João P De Lima
- Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculty of Medical Sciences, NOVA University of Lisbon, 1169-056 Lisbon, Portugal
| | - Alice Reichert
- Department of Clinical Haematology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449-005 Lisbon, Portugal
| | - Fernando Lima
- Department of Clinical Haematology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449-005 Lisbon, Portugal
| | - Esmeraldina Júnior
- Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449-005 Lisbon, Portugal
| | - José Rueff
- Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculty of Medical Sciences, NOVA University of Lisbon, 1169-056 Lisbon, Portugal
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14
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Rank L, Veith S, Gwosch EC, Demgenski J, Ganz M, Jongmans MC, Vogel C, Fischbach A, Buerger S, Fischer JMF, Zubel T, Stier A, Renner C, Schmalz M, Beneke S, Groettrup M, Kuiper RP, Bürkle A, Ferrando-May E, Mangerich A. Analyzing structure-function relationships of artificial and cancer-associated PARP1 variants by reconstituting TALEN-generated HeLa PARP1 knock-out cells. Nucleic Acids Res 2016; 44:10386-10405. [PMID: 27694308 PMCID: PMC5137445 DOI: 10.1093/nar/gkw859] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 09/05/2016] [Accepted: 09/16/2016] [Indexed: 12/17/2022] Open
Abstract
Genotoxic stress activates PARP1, resulting in the post-translational modification of proteins with poly(ADP-ribose) (PAR). We genetically deleted PARP1 in one of the most widely used human cell systems, i.e. HeLa cells, via TALEN-mediated gene targeting. After comprehensive characterization of these cells during genotoxic stress, we analyzed structure–function relationships of PARP1 by reconstituting PARP1 KO cells with a series of PARP1 variants. Firstly, we verified that the PARP1\E988K mutant exhibits mono-ADP-ribosylation activity and we demonstrate that the PARP1\L713F mutant is constitutively active in cells. Secondly, both mutants exhibit distinct recruitment kinetics to sites of laser-induced DNA damage, which can potentially be attributed to non-covalent PARP1–PAR interaction via several PAR binding motifs. Thirdly, both mutants had distinct functional consequences in cellular patho-physiology, i.e. PARP1\L713F expression triggered apoptosis, whereas PARP1\E988K reconstitution caused a DNA-damage-induced G2 arrest. Importantly, both effects could be rescued by PARP inhibitor treatment, indicating distinct cellular consequences of constitutive PARylation and mono(ADP-ribosyl)ation. Finally, we demonstrate that the cancer-associated PARP1 SNP variant (V762A) as well as a newly identified inherited PARP1 mutation (F304L\V762A) present in a patient with pediatric colorectal carcinoma exhibit altered biochemical and cellular properties, thereby potentially supporting human carcinogenesis. Together, we establish a novel cellular model for PARylation research, by revealing strong structure–function relationships of natural and artificial PARP1 variants.
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Affiliation(s)
- Lisa Rank
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Sebastian Veith
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Research Training Group 1331, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Eva C Gwosch
- Bioimaging Center, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Konstanz Research School Chemical Biology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Janine Demgenski
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Magdalena Ganz
- Bioimaging Center, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Konstanz Research School Chemical Biology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Marjolijn C Jongmans
- Department of Human Genetics, Radboud University Medical Center Nijmegen, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.,Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherland
| | - Christopher Vogel
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Arthur Fischbach
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Konstanz Research School Chemical Biology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Stefanie Buerger
- FlowKon FACS Facility, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Jan M F Fischer
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Konstanz Research School Chemical Biology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Tabea Zubel
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Konstanz Research School Chemical Biology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Anna Stier
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Christina Renner
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Michael Schmalz
- Center of Applied Photonics, Department of Physics, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Sascha Beneke
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Ecotoxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Marcus Groettrup
- FlowKon FACS Facility, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.,Immunology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Roland P Kuiper
- Department of Human Genetics, Radboud University Medical Center Nijmegen, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Alexander Bürkle
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Elisa Ferrando-May
- Bioimaging Center, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
| | - Aswin Mangerich
- Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
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15
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Single nucleotide polymorphisms in DNA repair genes and putative cancer risk. Arch Toxicol 2016; 90:2369-88. [PMID: 27334373 DOI: 10.1007/s00204-016-1771-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 06/15/2016] [Indexed: 02/07/2023]
Abstract
Single nucleotide polymorphisms (SNPs) are the most frequent type of genetic alterations between individuals. An SNP located within the coding sequence of a gene may lead to an amino acid substitution and in turn might alter protein function. Such a change in protein sequence could be functionally relevant and therefore might be associated with susceptibility to human diseases, such as cancer. DNA repair mechanisms are known to play an important role in cancer development, as shown in various human cancer syndromes, which arise due to mutations in DNA repair genes. This leads to the question whether subtle genetic changes such as SNPs in DNA repair genes may contribute to cancer susceptibility. In numerous epidemiological studies, efforts have been made to associate specific SNPs in DNA repair genes with altered DNA repair and cancer. The present review describes some of the common and most extensively studied SNPs in DNA repair genes and discusses whether they are functionally relevant and subsequently increase the likelihood that cancer will develop.
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16
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Jia ZF, Zhang SL, Cao XY, Zhou BS, Jiang J. Interaction between Helicobacter pylori and host genetic variants in gastric carcinogenesis. Future Oncol 2016; 12:2127-34. [PMID: 27324311 DOI: 10.2217/fon-2016-0233] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori (H. pylori) is the definite carcinogen of gastric cancer. H. pylori infection induces chronic inflammation, causes DNA damage and aberrant methylation of genes and these pathways are involved in H. pylori-related gastric carcinogenesis. Polymorphisms of the genes involved in these pathways could alter susceptibility to gastric cancer. In this mini review, we focused on the role of polymorphisms in these genes on the susceptibility to gastric cancer, with a particular emphasis on their possible interactions with H. pylori infection. We found that many studies on this theme did not simultaneously report H. pylori infection and the interactions remained inconclusive.
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Affiliation(s)
- Zhi-Fang Jia
- Division of Clinical Research, First Hospital of Jilin University, Changchun 130021, China.,Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110112, China
| | - Song-Ling Zhang
- Department of Gynecological Oncology, First Hospital of Jilin University, Changchun 130021, China
| | - Xue-Yuan Cao
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun 130021, China
| | - Bao-Sen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110112, China
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun 130021, China
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17
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Larionov AV, Sinitsky MY, Druzhinin VG, Volobaev VP, Minina VI, Asanov MA, Meyer AV, Tolochko TA, Kalyuzhnaya EE. DNA excision repair and double-strand break repair gene polymorphisms and the level of chromosome aberration in children with long-term exposure to radon. Int J Radiat Biol 2016; 92:466-74. [DOI: 10.1080/09553002.2016.1186303] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Aleksey V. Larionov
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
| | - Maxim Y. Sinitsky
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
- Federal State Budget Scientific Institution, The Federal Research Center of Coal and Coal Chemistry of Siberian Branch of the Russian Academy of Sciences, Kemerovo, Russian Federation
- Laboratory of Genome Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation
| | - Vladimir G. Druzhinin
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
- Federal State Budget Scientific Institution, The Federal Research Center of Coal and Coal Chemistry of Siberian Branch of the Russian Academy of Sciences, Kemerovo, Russian Federation
| | - Valentin P. Volobaev
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
| | - Varvara I. Minina
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
- Federal State Budget Scientific Institution, The Federal Research Center of Coal and Coal Chemistry of Siberian Branch of the Russian Academy of Sciences, Kemerovo, Russian Federation
| | - Maxim A. Asanov
- Federal State Budget Scientific Institution, The Federal Research Center of Coal and Coal Chemistry of Siberian Branch of the Russian Academy of Sciences, Kemerovo, Russian Federation
| | - Alina V. Meyer
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
| | - Tatiana A. Tolochko
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
| | - Ekaterina E. Kalyuzhnaya
- Department of Genetics, Biology Faculty, Kemerovo State University, Kemerovo, Russian Federation
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18
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Poly(ADP-Ribose) Polymerase in Cervical Cancer Pathogenesis: Mechanism and Potential Role for PARP Inhibitors. Int J Gynecol Cancer 2016; 26:763-9. [DOI: 10.1097/igc.0000000000000654] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AbstractTreatment options for disease recurrence of women treated for locally advanced and advanced cervical cancer are very limited—largely palliative chemotherapy. The low efficacy of the currently available drugs raises the need for new targeted agents. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutic agents in cancers associated with defects in DNA repair. Their therapeutic potential in cervical cancer is currently being evaluated in 3 ongoing clinical trials. Here we review the available information regarding all the aspects of PARP in cervical intraepithelial neoplasia and invasive cervical cancer, from expression and the mechanism of action to the role of the polymorphisms in the pathogenesis of the disease, as well as the potential of the inhibitors. We finally propose a new unifying theory regarding the role of PARPs in the development of cervical carcinomas.
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19
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RecQ helicases and PARP1 team up in maintaining genome integrity. Ageing Res Rev 2015; 23:12-28. [PMID: 25555679 DOI: 10.1016/j.arr.2014.12.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Revised: 12/18/2014] [Accepted: 12/22/2014] [Indexed: 01/04/2023]
Abstract
Genome instability represents a primary hallmark of aging and cancer. RecQL helicases (i.e., RECQL1, WRN, BLM, RECQL4, RECQL5) as well as poly(ADP-ribose) polymerases (PARPs, in particular PARP1) represent two central quality control systems to preserve genome integrity in mammalian cells. Consistently, both enzymatic families have been linked to mechanisms of aging and carcinogenesis in mice and humans. This is in accordance with clinical and epidemiological findings demonstrating that defects in three RecQL helicases, i.e., WRN, BLM, RECQL4, are related to human progeroid and cancer predisposition syndromes, i.e., Werner, Bloom, and Rothmund Thomson syndrome, respectively. Moreover, PARP1 hypomorphy is associated with a higher risk for certain types of cancer. On a molecular level, RecQL helicases and PARP1 are involved in the control of DNA repair, telomere maintenance, and replicative stress. Notably, over the last decade, it became apparent that all five RecQL helicases physically or functionally interact with PARP1 and/or its enzymatic product poly(ADP-ribose) (PAR). Furthermore, a profound body of evidence revealed that the cooperative function of RECQLs and PARP1 represents an important factor for maintaining genome integrity. In this review, we summarize the status quo of this molecular cooperation and discuss open questions that provide a basis for future studies to dissect the cooperative functions of RecQL helicases and PARP1 in aging and carcinogenesis.
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20
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Sistigu A, Manic G, Obrist F, Vitale I. Trial watch - inhibiting PARP enzymes for anticancer therapy. Mol Cell Oncol 2015; 3:e1053594. [PMID: 27308587 DOI: 10.1080/23723556.2015.1053594] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 05/16/2015] [Accepted: 05/18/2015] [Indexed: 12/25/2022]
Abstract
Poly(ADP-ribose) polymerases (PARPs) are a members of family of enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) and/or mono(ADP-ribosyl)ation (MARylation), two post-translational protein modifications involved in crucial cellular processes including (but not limited to) the DNA damage response (DDR). PARP1, the most abundant family member, is a nuclear protein that is activated upon sensing distinct types of DNA damage and contributes to their resolution by PARylating multiple DDR players. Recent evidence suggests that, along with DDR, activated PARP1 mediates a series of prosurvival and proapoptotic processes aimed at preserving genomic stability. Despite this potential oncosuppressive role, upregulation and/or overactivation of PARP1 or other PARP enzymes has been reported in a variety of human neoplasms. Over the last few decades, several pharmacologic inhibitors of PARP1 and PARP2 have been assessed in preclinical and clinical studies showing potent antineoplastic activity, particularly against homologous recombination (HR)-deficient ovarian and breast cancers. In this Trial Watch, we describe the impact of PARP enzymes and PARylation in cancer, discuss the mechanism of cancer cell killing by PARP1 inactivation, and summarize the results of recent clinical studies aimed at evaluating the safety and therapeutic profile of PARP inhibitors in cancer patients.
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Affiliation(s)
| | - Gwenola Manic
- Regina Elena National Cancer Institute , Rome, Italy
| | - Florine Obrist
- Université Paris-Sud/Paris XI, Le Kremlin-Bicêtre, France; INSERM, UMRS1138, Paris, France; Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France
| | - Ilio Vitale
- Regina Elena National Cancer Institute, Rome, Italy; Department of Biology, University of Rome "TorVergata", Rome, Italy
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