• AML
• FLT3-TKD
• del 7
• dyskeratosis congenita
• telomere

Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.

Dyskerin is a protein involved in the formation of small nucleolar and small Cajal body ribonucleoproteins. These complexes participate in RNA pseudouridylation and are also components of the telomerase complex required for telomere elongation. Dyskerin mutations cause a rare disease, X-linked dyskeratosis congenita, with no curative treatment. The social amoeba Dictyostelium discoideum contains a gene coding for a dyskerin homologous protein. In this article D. discoideum mutant strains that have mutations corresponding to mutations found in dyskeratosis congenita patients are described. The phenotype of the mutant strains has been studied and no alterations were observed in pseudouridylation activity and telomere structure. Mutant strains showed increased proliferation on liquid culture but reduced growth feeding on bacteria. The results obtained indicated the existence of increased DNA damage response and reactive oxygen species, as also reported in human Dyskeratosis congenita cells and some other disease models. These data, together with the haploid character of D. discoideum vegetative cells, that resemble the genomic structure of the human dyskerin gene, located in the X chromosome, support the conclusion that D. discoideum can be a good model system for the study of this disease.

• DNA damage
• dictyostelium
• dyskeratosis congenita
• dyskerin
• oxidative stress
• pseudouridylation
• telomere
• telomere biology disorder

• HDV ribozyme
• cotranscriptional
• folding kinetics
• pathway
• pseudoknot

• Catalytic Domain
• Hepatitis Delta Virus/chemistry
• Hepatitis Delta Virus/genetics
• Kinetics
• Models, Molecular
• Nucleic Acid Conformation
• RNA Folding
• RNA, Catalytic/chemistry
• RNA, Catalytic/genetics
• RNA, Viral/chemistry
• RNA, Viral/genetics
• Transcription, Genetic

• National Natural Science Foundation of China

• CST
• H/ACA RNP
• electron microscopy
• replication protein A
• telomerase RNA
• telomerase reverse transcriptase

• Humans
• Models, Molecular
• Protein Domains
• Protozoan Proteins/chemistry
• RNA/chemistry
• Telomerase/chemistry
• Tetrahymena/enzymology

• R01 GM048123 NIGMS NIH HHS
• T32 GM007185 NIGMS NIH HHS

• Cajal body
• SMN
• WRAP53
• coilin
• phosphorylation
• post-translational modification
• telomerase

• Caenorhabditis elegans
• QTL
• shelterin
• telomere length
• whole-genome sequence

• Bone Diseases, Metabolic/diagnosis
• Bone Diseases, Metabolic/genetics
• Bone Marrow/abnormalities
• Cell Cycle Proteins/genetics
• Child
• Dyskeratosis Congenita/diagnosis
• Dyskeratosis Congenita/genetics
• Female
• Humans
• Nuclear Proteins/genetics
• Optic Atrophy/diagnosis
• Optic Atrophy/genetics
• Retina
• Retinitis Pigmentosa/diagnosis
• Retinitis Pigmentosa/genetics
• Visual Acuity

• Genetic Diseases, Inborn/genetics
• Genetics, Medical
• Genomic Instability
• Humans
• Mutation
• Telomere/metabolism
• Telomere Homeostasis
• Telomere-Binding Proteins/genetics
• Telomere-Binding Proteins/metabolism

• 104558 Wellcome Trust
• 11581 Cancer Research UK

Acquisition of pluripotency is driven largely at the transcriptional level by activators OCT4, SOX2, and NANOG that must in turn cooperate with diverse coactivators to execute stem cell-specific gene expression programs. Using a biochemically defined in vitro transcription system that mediates OCT4/SOX2 and coactivator-dependent transcription of the Nanog gene, we report the purification and identification of the dyskerin (DKC1) ribonucleoprotein complex as an OCT4/SOX2 coactivator whose activity appears to be modulated by a subset of associated small nucleolar RNAs (snoRNAs). The DKC1 complex occupies enhancers and regulates the expression of key pluripotency genes critical for self-renewal in embryonic stem (ES) cells. Depletion of DKC1 in fibroblasts significantly decreased the efficiency of induced pluripotent stem (iPS) cell generation. This study thus reveals an unanticipated transcriptional role of the DKC1 complex in stem cell maintenance and somatic cell reprogramming.

DOI:http://dx.doi.org/10.7554/eLife.03573.001

The stem cells found in an embryo are able to develop into any of the cell types found in the body of the animal: an ability called pluripotency. When a cell becomes a specialized cell type, such as a nerve cell or a muscle cell, it loses this ability. However, mature cells can be reprogrammed back to a pluripotent state by artificially introducing certain proteins (known as ‘reprogramming factors’) into the mature cells.

A core group of reprogramming factors are known to activate networks of genes that are normally only expressed in stem cells, and by doing so trigger and maintain a pluripotent state. Other proteins help these core factors to regulate these networks of genes. In 2011, researchers discovered that a protein complex called XPC—which is normally involved in DNA repair—also helps two core reprogramming factors to activate an important gene related to pluripotency.

Now, Fong et al., including several of the researchers involved in the 2011 work, have identified another unexpected partner for the same two core reprogramming factors. The protein complex, called DKC1, has a number of known functions related to the processing of RNA molecules. This complex has also been linked to a fatal, rare human disorder called dyskeratosis congenita—a condition that affects many parts of the body, including the skin and bone marrow. Fong et al. found that when embryonic stems cells from mice are depleted of the DKC1 complex, the activation of important pluripotency-related genes by two of the core reprogramming factors is markedly reduced.

The XPC and DKC1 protein complexes were found to interact in pluripotent cells, and together they can activate a pluripotency-related gene to a greater extent than either can individually. Fong et al. propose that DKC1 binds to XPC, which in turn binds to two of the core reprogramming factors.

The DKC1 complex also binds to RNA molecules, and Fong et al. found that when the DKC1 complex binds to certain RNAs it is more able to help reprogramming factors activate pluripotency-related genes. On the other hand, other RNA molecules seem to inhibit the complex's ability to activate these genes.

Mutations identified in people with dyskeratosis congenita can prevent the DKC1 complex from binding to a subset of human RNA molecules. Moreover, the activity of stem cells is impaired in people with this developmental condition. As such, one of the next challenges will be to investigate if these mutations and RNA binding could be linked to problems with the activation of genes related to pluripotency in stem cells.

DOI:http://dx.doi.org/10.7554/eLife.03573.002

• biochemistry
• developmental biology
• embryonic stem cells
• human
• induced pluripotent stem cells
• mouse
• non-coding RNA
• pluripotency
• priviledged somatic cell state
• stem cells
• transcriptional coactivators

• anti-glaucoma drugs
• anticipation
• myocilin
• phenotype

• Aplastic anemia
• Bone marrow failure
• Dyskeratosis congenita
• Leukemia
• Myelodysplastic syndrome

• Animals
• Hematologic Diseases/genetics
• Hematologic Diseases/pathology
• Humans
• Telomerase/metabolism
• Telomere/genetics
• Telomere/metabolism
• Telomere/pathology

• DKC1
• X-linked dyskeratosis congenita
• dyskerin
• ribosomal RNA
• ribosomes

Genetic instability is the driving force of the malignant progression of cancer cells. Recently, replication stress has attracted much attention as a source of genetic instability that gives rise to an accumulation of mutations during the lifespan of individuals. However, the molecular details of the process are not fully understood. Here, recent progress in understanding how genetic alterations accumulate at telomeres will be reviewed. In particular, two aspects of telomere replication will be discussed in this context, covering conventional semi-conservative replication, and DNA synthesis by telomerase plus the C-strand fill-in reactions. Although these processes are seemingly telomere-specific, I will emphasize the possibility that the molecular understanding of the telomere events may shed light on genetic instability at other genetic loci in general.

Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

• Age of Onset
• Aged
• Aged, 80 and over
• Anticipation, Genetic/genetics
• Child
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Female
• Humans
• Male
• Middle Aged
• Pedigree
• Telomere/genetics
• Telomere Shortening

DNA damage contributes to cancer development and aging. Congenital syndromes that affect DNA repair processes are characterized by cancer susceptibility, developmental defects, and accelerated aging (Schumacher et al., 2008). DNA damage interferes with DNA metabolism by blocking replication and transcription. DNA polymerase blockage leads to replication arrest and can gives rise to genome instability. Transcription, on the other hand, is an essential process for utilizing the information encoded in the genome. DNA damage that interferes with transcription can lead to apoptosis and cellular senescence. Both processes are powerful tumor suppressors (Bartek and Lukas, 2007). Cellular response mechanisms to stalled RNA polymerase II complexes have only recently started to be uncovered. Transcription-coupled DNA damage responses might thus play important roles for the adjustments to DNA damage accumulation in the aging organism (Garinis et al., 2009). Here we review human disorders that are caused by defects in genome stability to explore the role of DNA damage in aging and disease. We discuss how the nucleotide excision repair system functions at the interface of transcription and repair and conclude with concepts how therapeutic targeting of transcription might be utilized in the treatment of cancer.

• DNA damage
• DNA repair
• cancer
• genetic
• progeria
• transcription

Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.

• Anticipation
• MMR genes
• lynch syndrome
• microsatellite instability
• telomere dynamics.
• telomere length

• Dyskeratosis congenita
• Induced pluripotent stem cells
• Marrow failure
• Telomeres, Telomerase

• telomere
• telomere biology disorder
• dyskeratosis congenita
• bone marrow failure
• idiopathic pulmonary fibrosis

• Chromosome Disorders/genetics
• Chromosome Disorders/pathology
• Genetic Predisposition to Disease
• Humans
• Inheritance Patterns/genetics
• Mutation
• Telomerase/genetics
• Telomerase/metabolism
• Telomere/genetics
• Telomere/pathology

• ZIA CP010190 Intramural NIH HHS

• Anemia, Aplastic/genetics
• Child
• Dyskeratosis Congenita/genetics
• Heterozygote
• Humans
• Male
• Mutation, Missense
• Sequence Analysis, DNA
• Telomerase/genetics
• Telomere/pathology

• GGP07242 Telethon

• structural genomics
• protein function prediction
• pua domain-like domains
• x-ray crystallography
• nmr

• Amino Acid Sequence
• Binding Sites/genetics
• Conserved Sequence/genetics
• Databases, Protein
• Eukaryotic Cells/chemistry
• Eukaryotic Cells/metabolism
• Genomics/methods
• Ligands
• Models, Molecular
• Molecular Sequence Data
• Phylogeny
• Prokaryotic Cells/chemistry
• Prokaryotic Cells/metabolism
• Protein Structure, Tertiary
• Proteins/chemistry
• Proteins/classification
• Proteins/genetics
• RNA-Binding Proteins/chemistry
• RNA-Binding Proteins/genetics
• Sequence Homology, Amino Acid
• Structure-Activity Relationship

• U54 GM074958 NIGMS NIH HHS
• R01-GM079767 NIGMS NIH HHS
• R01 GM079767 NIGMS NIH HHS
• U54-GM074958-01 NIGMS NIH HHS
• R01 LM007329 NLM NIH HHS
• R01-LM07329 NLM NIH HHS

• x-chromosome inactivation
• x;1 translocation
• xq28 functional disomy
• dkc1

• Abnormalities, Multiple/genetics
• Cell Cycle Proteins/genetics
• Chromosome Breakage
• Chromosome Mapping
• Chromosomes, Artificial, Bacterial
• Chromosomes, Human, X
• DNA, Complementary
• Dosage Compensation, Genetic
• Female
• Gene Dosage
• Humans
• In Situ Hybridization, Fluorescence
• Nuclear Proteins/genetics
• Oligonucleotide Array Sequence Analysis
• Translocation, Genetic
• Uniparental Disomy/genetics
• X Chromosome Inactivation

• K02DE015291 NIDCR NIH HHS
• R01 DE014667 NIDCR NIH HHS
• R01 DE014677 NIDCR NIH HHS
• P60 DE013076 NIDCR NIH HHS
• K02 DE015291 NIDCR NIH HHS
• R01 ES014677 NIEHS NIH HHS

• ATPases Associated with Diverse Cellular Activities
• Adenosine Triphosphatases/chemistry
• Adenosine Triphosphatases/isolation & purification
• Adenosine Triphosphatases/metabolism
• Carrier Proteins/chemistry
• Carrier Proteins/isolation & purification
• Carrier Proteins/metabolism
• Cell Cycle
• Cell Cycle Proteins/metabolism
• Chromatography, Affinity
• DNA Helicases/chemistry
• DNA Helicases/isolation & purification
• DNA Helicases/metabolism
• HeLa Cells
• Holoenzymes/chemistry
• Holoenzymes/metabolism
• Humans
• Models, Biological
• Models, Molecular
• Nuclear Proteins/metabolism
• RNA/metabolism
• S Phase
• Telomerase/chemistry
• Telomerase/metabolism
• Telomere/metabolism

• T32 GM007365 NIGMS NIH HHS
• R01 CA106995 NCI NIH HHS
• R01 CA111691 NCI NIH HHS
• R01 CA125453 NCI NIH HHS
• N01-CO-12400 NCI NIH HHS
• CA125453 NCI NIH HHS
• CA111691 NCI NIH HHS
• GM07365 NIGMS NIH HHS
• N01 CO012400 NCI NIH HHS