Jun Yang, Zheng-Ping Xu, Yun Huang, Ying-Nian Yu, Department of Pathology and Pathophysiology, and Department of Public Health, School of Medicine, Zhejiang University, Hangzhou, 310031, Zhejiang Province, China
Hope E. Hamrick, Department of Psychology, Wellesley College, Wellesley, MA, 02481, U S A
Penelope J. Duerksen-Hughes, Center for Molecular Biology and Gene Therapy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, U S A
Supported by National Key Basic Research and Development Program No. 2002CB512901, China; National Natural Science Foundation No. 30300277, China; the Initial Funds for Returned Overseas Chinese Scholar from Zhejiang University and Ministry of Education, China
Correspondence to: Dr. Ying-Nian Yu, Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, 353 Yanan Road, Hangzhou, 310031, Zhejiang Province, China.  ynyu@hzcnc.com
Telephone: +86-571-8721 7149    Fax: +86-571-8721 7149
Received: 2003-07-17    Accepted: 2003-08-18

Abstract
Cellular response to genotoxic stress is a very complex process, and it usually starts with the "sensing" or "detection" of the DNA damage, followed by a series of events that include signal transduction and activation of transcription factors. The activated transcription factors induce expressions of many genes which are involved in cellular functions such as DNA repair, cell cycle arrest, and cell death. There have been extensive studies from multiple disciplines exploring the mechanisms of cellular genotoxic responses, which have resulted in the identification of many cellular components involved in this process, including the mitogen-activated protein kinases (MAPKs) cascade. Although the initial activation of protein kinase cascade is not fully understood, human protein kinases ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) are emerging as potential sensors of DNA damage. Current progresses in ATM/ATR research and related signaling pathways are discussed in this review, in an effort to facilitate a better understanding of genotoxic stress response.

Yang J, Xu ZP, Huang Y, Hamrick HE, Duerksen-Hughes PJ, Yu YN. ATM and ATR: Sensing DNA damage. World J Gastroenterol  2004; 10(2): 155-160
http://www.wjgnet.com/1007-9327/10/155.asp

INTRODUCTION
Cellular response to genotoxic stress is a very complex process.  However, it can be "simply" envisioned as a signal transduction cascade in which DNA lesions act as the initial signal that is detected by sensors and passed down through transducers.  Eventually the effectors receive the signal and execute various cellular functions (Figure 1). Much knowledge has been gained over the years concerning the signal transducers, and a large group of serine-threonine protein kinases, namely the mitogen-activated protein kinases (MAPKs), along with their upstream kinases, have been shown to play prominent roles in cellular genotoxic responses^[1]. Three major classes of MAPKs, i.e., extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 (also known as SAPK2, RK, CSBP, or Mxi2), could all be activated by various genotoxic stresses^[1-7]. Although the precise mechanism has not been fully understood, it is known that damage to cellular DNA somehow leads to the activation of a group of serine-threonine kinases called MAPK kinase kinases (MAPKKK, or MEKK, MEK kinase), which phosphorylate the downstream dual-specificity kinases called MAPK kinases (MAPKK, or MEK, MAPK/ERK kinase). These MAPKKs then phosphorylate the threonine and tyrosine residues in MAPKs. This three-component module could be assembled together by scaffold proteins that ensure the efficiency and specificity of each individual MAPK pathway^[8-10]. The activated MAPKs then translocate to the nucleus and phosphorylate scores of target proteins, including many transcription factors. Among these transcription factors is the tumor suppressor p53 protein, which plays such an important role in the genotoxic stress response that has earned the reputation as the "universal sensor for genotoxic stress"^[2,11,12].

Figure 1(PDF) A general schematic representation of cellular responses to genotoxic stress. Ultraviolet (UV), ionizing radiation (IR), and various chemicals can induce DNA damage, such as double strand breaks (DSBs), which can be detected by "sensors". This generates some signal that can be transduced by the transducers to effector molecules. Finally, there is the presence of an attenuation mechanism to control the cellular response to genotoxic stress.

    Although studies on MAPKs have provided a lot useful information about signal transducers, the initial sensors for DNA damage remain to be identified. Recently, it has been proposed that some multi-protein complexes that are involved in DNA maintenance or repair, such as the Rad family member Rad1, 9, 17, 26, and Hus1, might function as DNA damage sensors^[13-18]. Members of the phosphatidylinositol 3-kinase (PI-3) superfamily, which are activated at the very early stages of DNA damage response, could also serve as sensors, as well as initiators, of the ensuing cellular genotoxic stress response, including ATM and ATR in humans^[19]. Although these proteins share the PI-3-like kinase domain, they could not function as lipid kinases, but rather as serine-threonine protein kinases^[14,20-25].

ATM AND ATR
Biochemistry of ATM and ATR
One distinguishing characteristic of the PI-3 family members is their unusually large size, which ranges from around 300 kDa to over 500 kDa.  ATM is a 3 056 amino acid (aa) protein while ATR is a 2 644 aa protein, and both have a C-terminal catalytic domain (-300 aa) which is flanked by two loosely conserved domains. Although it has not been known how exactly these two kinases sense the DNA damage, it is clear that both kinases can be activated by DNA damage. However, it has been found that ATM responds primarily to double-strand breaks induced by ionizing irradiation (IR), while ATR also reacts to UV or stalled replication forks^{[13,14,26-29]}.

Activation of ATM and ATR
Several mechanisms have been proposed for the activation of ATM and ATR by DNA damage: a) direct activation through interaction with damaged DNA, b) indirect activation through interaction with DNA repair or maintenance proteins, or c) a combination of both^[30]. Existing experimental data support the third mechanism, that they are activated both through interactions with DNA and members of the repair complexes.  For example, ATM could bind directly to DNA. Furthermore, pre-treatment of DNA-cellulose matrix with IR or restriction enzymes could stimulate ATM binding, suggesting that ATM binds to DNA ends^[31,32]. ATR could also bind to DNA, with a higher affinity to UV-damaged than undamaged DNA. In addition, damaged DNA could stimulate the kinase activity of ATR to a significantly higher level than undamaged DNA^[33,34]. ATM and ATR also interact with many proteins that co-localize at the site of DNA damage. For example, ATM as a part of a super protein complex called BRCA1-associated genome surveillance complex (BASC), is involved in the recognition and repair of aberrant DNA structures. It has been found  this complex contains several other proteins such as breast cancer gene 1 (BRCA1), mismatch-repair protein hRad50, and BLM helicase^[35]. ATM could bind to histone deacetylase HDAC1 both in vitro and in vivo, and the extent of this association was increased after exposure of MRC5CV1 human fibroblasts to IR^[36]. ATR was also able to bind to Rad17^[37] and BRCA1^[38], and associated with components of the nucleosome remodeling and deacetylating (NRD) complex such as chromodomain- helicase-DNA-binding protein 4 (CHD4) and histone-deacetylase-2 (HDAC2)^[39]. All these data support the model that multiple checkpoint protein complexes localize at the sites of DNA damage independently and interact to trigger the checkpoint-signaling cascade.

Interaction with c-Abl
c-Abl, a non-receptor tyrosine kinase that is ubiquitously expressed and localized in both nucleus and cytoplasm, could be up-regulated following exposure to IR or genotoxic chemicals such as cisplatin, methyl methane sulfonate (MMS), mitomycin-C, hydrogen peroxide, but not UV^[3,40-42]. IR-induced activation of c-Abl has been shown to require the involvement of ATM in some cases, with ATM phosphorylating serine residue 465 located within the kinase domain of c-Abl^[43-45].  However, other studies found that c-Abl was not essential for ATM function in chromosomal maintenance, suggesting that c-Abl and ATM are at least partially independent^[46].
     An important effect which has been found following the activation of c-Abl, is the induction of cell cycle arrest in a p53-dependent manner, with the possible involvement of Rb, but not p21Cip^[47,48]. c-Abl could directly interact with and phosphorylate p53, and regulate the level of p53 by preventing its nuclear export and ubiquitination-dependent degradation^[49,50]. It could also induce apoptosis in response to DNA damage^[51,52], although this activity involved collaboration with p73 more than p53^[53-55]. c-Abl binds to p73 through its Src-homology (SH3) domain to phosphorylate p73 at tyrosine residues, which in turn activates p73-dependent apoptosis pathway.

Regulation of the tumor suppressor p53 protein
Since p53 is such an important mediator in cellular response to genotoxic stress, it is no wonder that ATM/ATR can regulate p53 activity at multiple levels (Figure 2). The most straightforward way to manage p53 is through direct interaction, e.g., phosphorylation of p53. Both ATM and ATR have been shown to phosphorylate p53 protein at serine 15 to enhance its transactivating activity^[56-59]. ATM is also required for dephosphorylation of Ser 376, which can create a binding site for 14-3-3 protein. The association of p53 and 14-3-3 could increase the affinity of p53 for its specific DNA sequence, therefore enhancing its transcriptional activity[60]. Other sites that could be phosphorylated by ATM on p53 include Ser 6, 9, 46, and Thr 18, which may be important for the apoptotic activity of p53 (Ser 46) or may enhance the acetylation of p53 (Ser 6, 9, Thr18)^[61]. In addition, ATM/ATR could regulate p53 through the action of other kinases. For example, ATM-activated c-Abl could phosphorylate p53 at Ser 20, which is important for the stabilization of p53 since this modification interferes with the binding between p53 and its regulator murine double minute 2 (Mdm2)^[49,62]. ATM-activated Chk2 could also phosphorylate p53 protein at Ser 20 and possibly at other sites, leading to the activation of p53^[63-65]. Furthermore, ATM has been found able to bind and phosphorylate Mdm2 and HDM2 (the human homologue of Mdm2), thus inhibiting p53 degradation and promoting its accumulation in cells^[66-68].

Figure 2(PDF) Regulation of p53 protein by ATM and ATR. ATM and ATR can influence the activity of p53 directly through phosphorylation or indirectly through the action of other kinases.  Furthermore, ATM can regulate p53 through phosphorylation of Mdm2 molecule, the negative regulator of p53, which can be up-regulated by p53.

Activation of MAPKs
Accumulative data support the notion that the activation of MAPKs in response to genotoxic stress is ATM/ATR dependent. For example, DNA damaging stimuli, including etoposide (ETOP), adriamycin (ADR), IR, and UV could activate ERK1/2 in primary (MEF and IMR90), immortalized (NIH3T3) and transformed (MCF-7) cells. It has further been shown that ERK activation in response to ETOP could be abolished in ATM-/- fibroblasts (GM05823) independenty of p53^[69]. UVA (320-400 nm) triggered ATM-dependent p53 phosphorylation and JNK activation that resulted in apoptosis, while ATR was required for UVC (200-290 nm)-mediated p53 phosphorylation and JNK activation^[70]. In addition, activation of ATM by gamma irradiation could lead to the activation of MKK6 and p38g isoform, and that activation of both MKK6 and p38g was essential for the proper regulation of G2 checkpoint in mammalian cells^[71].
     Although the link between ATM/ATR and MAPKs has been established, it is still not clear how ATM/ATR activates MAPKs. In general, MAPK pathways are activated by extracellular signals or signals generated in the cytoplasm, and then the activated MAPKs transduce the specific "messages" to the nucleus. However, in response to genotoxic stress, the signal seems to flow from the nucleus to the cytoplasm to activate MAPKs. In this case, c-Abl kinase may provide an explanation. It has been found that c-Abl can activate p38 through MKK6^[72-74], and JNK by translocating from nucleus to cytoplasm to phosphorylate hematopoietic progenitor kinase (HPK1), an upstream kinase of JNK^[75]. Therefore, c-Abl may fulfill a role as the message carrier to transduce signals between subcellular locations. This may further explain why in response to genotoxic stress the activation of p38 was rather late (- 1 h) and prolonged^[71], while the cytokine activation of p38 was rapid and transient (maximum around 30-60 min)^[76].
      In addition to their ability to activate MAPKs, ATM/ATR may also regulate these kinases through their negative regulators, the dual specificity of phosphatase MAPK and phosphatase family (MKP). One member of the MKP family, MKP-5, is known to dephosphorylate and inactivate the stress-activated JNK and p38. The phosphorylation-dephosphorylation cycle of JNK and p38 stimulated by radiomimetic chemical neocarzinostatin (NCS), which can induce double strand breaks (DSBs), could be attenuated in A-T cell^s[77], further emphasizing the role of ATM as a master regulator in the cellular response to genotoxic stress.

Mutations in ATM in association with cancer
Homozygous mutations in the ATM gene can cause human genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar degeneration, immunodeficiency, cancer predisposition, and acute sensitivity to IR. The affected individual has been found to be prone to develop T cell pro-lymphocytic leukemia, B cell chronic lymphocytic leukemia, as well as sporadic colon cancer with microsatellite instability^[78]. Atm-deficient mice also showed a striking predisposition to lymphoid malignancies, particularly thymic lymphomas, to which they succumbed before the age of 1 year. However, much of the literature on ATM mutations and cancer was not about A-T patients, but was, instead, on heterozygous carriers of A-T mutations. For example, recent studies have found an unusually high occurrence of breast cancer in the relatives of A-T patients, and that loss of heterozygosity of ATM occurred frequently during the early stages of breast cancer development^[79]. Furthermore, heterozygous mice were more sensitive to radiation-induced cataracts than their wild-type counterparts^[80]. Spring et al, established a knock-in mouse mutant in which an inframe deletion was previously found to cause A-T in humans was induced. Mice homozygous for this mutation could produce small amounts of inactive ATM and usually showed the hallmarks of the Atm-knockout phenotype. Notably, mice heterozygous for this mutation were predisposed to various cancers, unlike the animals that carry a single knockout allele that does not produce any protein^[81]. Therefore, ATM heterozygotes in human population might also be more radiosensitive, and have a higher risk for cancer^[82](Figure 3).
      No human disease has been found to link to defects in ATR, although it was found that defects in ATR led to embryonic lethality in mice, suggesting that ATR is essential for of development of ATR^[83,84]. Nonetheless, it is known that over-expressing the inactive form of ATR had a dominant negative effect, causing increased sensitivity to DNA damaging stimuli and failure to activate cell cycle checkpoints in response to IR^[28,85]. Finally, over-expressing active ATR could restore S phase checkpoint defect in A-T cells, suggesting that ATM and ATR may complement each other in the cellular genotoxic stress response^[85].  

Figure 3(PDF) The relationship between ATM and carcinogenesis.

Down-regulation of ATM and ATR
Once the sensors detect DNA damage and initiate the signaling pathway, and the biological consequences (including DNA repair, cell cycle arrest, and apoptosis) take effect, the signals need to be inactivated or attenuated. The regulation of some downstream components in the cellular genotoxic stress response has been rather clearly defined, and usually involves a negative feedback mechanism. One such example is the p53-Mdm2 regulation loop. In this loop p53 could activate the expression of Mdm2, and Mdm2 could mediate the rapid degradation of p53 through the ubiquitin pathway^[62]. MAPKs have a similar feedback regulation mechanism with MKPs.  MAPKs could induce the expression of MKPs, and MKPs then could interact with specific MAPKs to deactivate them through dephosphorylation^[1]. On the other hand, the mechanisms for the regulation of ATM and ATR, remain obscure, although some recent studies have significantly advanced our understanding.
      In contrast to the vast volume of reports about the activation of ATM under genotoxic stress, very few studies have been conducted to evaluate how ATM was inactivated. The results from these studies so far all pointed toward inactivation of ATM through Caspase-mediated cleavage during apoptosis[86-88]. This same mechanism has also been shown to regulate many other proteins involved in apoptosis, including serine/threonine protein kinase Cd (PKCd), Mdm2, PARP, replication factor C, 70 kDa U1snRNP, fodrin and lamins^[87]. It was reported that during apoptosis induced by c-Myc or DNA-damaging agents (such as etoposide or IR), ATM but not ATR, was specifically cleaved by members of the Caspase family.  Detailed studies revealed that the Caspase responsible for this cleavage was either Caspase-3 or -7, but not Caspase-6. This cleavage abrogated the kinase activity of ATM to phosphorylate p53, although the resulting two fragments retained their DNA binding ability and interacted with each other. This finding led to the hypothesis that cleaved ATM protein, without its kinase activity, might act in a trans-dominant-negative fashion to compete with the intact ATM, thus preventing DNA repair and DNA damage signaling through its binding to DNA^[86-88]. 
      Even less information is available regarding the inactivation of ATR. However, the recent identification of an ATR-interacting protein (ATRIP) might provide a lead for future studies[89]. ATRIP is an 86-kDa protein with a coiled-coil domain near its N-terminal and its expression is regulated by ATR. The deletion of ATR mediated by Cre recombinase could cause the loss of both ATR and ATRIP expression, along with the loss of DNA damage checkpoint responses and cell death.  ATRIP could be phosphorylated by ATR and co-localized at intranuclear foci with ATR after DNA damage caused by hydroxyurea (HU), IR, or UV, or inhibition of DNA replication.  Conversely, ATRIP could also regulate the expression of ATR, as inhibition of ATRIP expression with small interference RNA (siRNA) would result in decreased ATR protein expression, while ATR mRNA levels would not be affected.  Interference with ATRIP function could cause the same loss of G2-M response to DNA damage as that seen in the case of ATR deletion, suggesting that these two proteins work as mutually dependent partners in cell cycle checkpoint pathways^[89].

CONCLUSION
Human cancer is a major health issue for society, causing millions of deaths each year and huge economical losses. Since most of human carcinogens are genotoxins^[90,91], considerable resources have been and are being expended in efforts to understand the mechanism of genotoxin-induced carcinogenesis, thus leading to a better prevention or even the treatment of cancer. Since the sensing of DNA damage is one of the earliest steps in the cellular response to gentoxic stress, identification of these "sensors" is the most prominent challenge. As discussed in this review, ATM and ATR are showing their promise as potential candidates. However, what we should keep in mind is that detection of DNA damage may not be such a simple process, and may require more than just one or two proteins to fulfill this role. Supporting this idea is the finding of "foci" at damaged DNA sites, where many proteins involved in DNA repair and maintenance aggregate.  It is more likely that interactions of these proteins, combined with some unidentified factors might function as DNA damage sensors^[92]. Further elucidation of these "foci" will be an exciting area for future research.

REFERENCES
1    Yang J, Yu Y, Duerksen-Hughes PJ. Protein kinases and their involvement in the cellular responses to genotoxic 
      stress. Mutat Res 2003; 543: 31-58
2    Liu Y, Guyton KZ, Gorospe M, Xu Q, Lee JC, Holbrook NJ. Differential activation of ERK, JNK/SAPK, and p38/CSBP/RK 
      map kinase family members during the cellular response to arsenite. Free Radic Biol Med 1996; 21: 771-781
3    Liu ZG, Baskaran R, Lea-Chou ET, Wood LD, Chen Y, Karin M, Wang JY. Three distinct signalling responses by murine
      fibroblasts to genotoxic stress. Nature 1996; 384: 273-276
4    Sanchez-Prieto R, Rojas JM, Taya Y, Gutkind JS. A role for the p38 mitogen-acitvated protein kinase pathway in the
      transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents. Cancer Res 2000; 60: 2464-2472
5    Kharbanda S, Saxena S, Yoshida K, Pandey P, Kaneki M, Wang Q, Cheng K, Chen YN, Campbell A, Sudha T, Yuan 
      ZM, Narula J, Weichselbaum R, Nalin C, Kufe D. Translocation of SAPK/JNK to mitochondria and interaction with 
      Bcl-x(L) in response to DNA damage. J Biol Chem 2000; 275: 322-327
6    Zhang Y, Zhong S, Dong Z, Chen N, Bode AM, Ma W, Dong Z. UVA induces Ser381 phosphorylation of p90RSK/
      MAPKAP-K1 via ERK and JNK pathways. J Biol Chem 2001; 276: 14572-14580
7    She QB, Chen N, Dong Z. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. 
      J Biol Chem 2000; 275: 20444-20449
8    Akechi M, Ito M, Uemura K, Takamatsu N, Yamashita S, Uchiyama K, Yoshioka K, Shiba T. Expression of JNK cascade
      scaffold protein JSAP1 in the mouse nervous system. Neurosci Res 2001; 39: 391-400
9    Tawadros T, Formenton A, Dudler J, Thompson N, Nicod P, Leisinger HJ, Waeber G, Haefliger JA. The scaffold protein 
      IB1/JIP-1 controls the activation of JNK in rat stressed urothelium. J Cell Sci 2002; 115(pt2): 385-393
10  Ito M, Akechi M, Hirose R, Ichimura M, Takamatsu N, Xu P, Nakabeppu Y, Tadayoshi S, Yamamoto K, Yoshioka K. 
      Isoforms of JSAP1 scaffold protein generated through alternative splicing. Gene 2000; 255: 229-234
11  Yang J, Duerksen-Hughes P. A new approach to identifying genotoxic carcinogens: p53 induction as an indicator of
      genotoxic damage. Carcinogenesis 1998; 19: 1117-1125
12  Wahl GM, Linke SP, Paulson TG, Huang LC. Maintaining genetic stability through TP53 mediated checkpoint control. 
      Cancer Surv 1997; 29: 183-219
13  Lowndes NF, Murguia JR. Sensing and responding to DNA damage. Curr Opin Genet Dev 2000; 10: 17-25
14  Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 2001; 15: 2177-2196
15  Rouse J, Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage. Science 
      2002; 297: 547-551
16  O'Connell MJ, Walworth NC, Carr AM. The G2-phase DNA-damgae checkpoint. Trends Cell Biol 2000; 10: 296-303
17  Green CM, Erdjument-Bromage H, Tempst P, Lowndes NF. A novel Rad24 checkpoint protein complex closely related 
      to replication factor C. Curr Biol 2000; 10: 39-42
18  Roos-Mattjus P, Vroman BT, Burtelow MA, Rauen M, Eapen AK, Karnitz LM. Genotoxin-induced Rad9-Hus1-Rad1 
      (9-1-1) chromatin association is an early checkpoint signaling event. J Biol Chem 2002; 277: 43809-43812
19  Durocher D, Jackson SP. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell 
      Biol 2001; 13: 225-231
20  Rotman G, Shiloh Y. ATM: a mediator of multiple responses to genotoxic stress. Oncogene 1999; 18: 6135-6144
21  Chan ED, Winston BW, Jarpe MB, Wynes MW, Riches DW. Preferential activation of the p46 isoform of JNK/SAPK in 
      mouse macrophages by TNF alpha. Proc Natl Acad Sci U S A 1997; 94: 13169-13174
22  Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF. ATR/ATM-
      mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 2001; 411: 969-974
23  Plumb MA, Smith GC, Cunniffe SM, Jackson SP, O'Neill P. DNA-PK activation by ionizing radiation-induced DNA
      single-strand breaks. Int J Radiat Biol 1999; 75: 553-561
24  Jackson SP. DNA-dependent protein kinase. Int J Biochem Cell Biol 1997; 29: 935-938
25  Gately DP, Hittle JC, Chan GK, Yen TJ. Characterization of ATM expression, localization, and associated DNA-dependent
      protein kinase activity. Mol Biol Cell 1998; 9: 2361-2374
26  Pandita TK, Lieberman HB, Lim DS, Dhar S, Zheng W, Taya Y, Kastan MB. Ionizing radiation activates the ATM 
      kinase throughout the cell cycle. Oncogene 2000; 19: 1386-1391
27  Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G. Nuclear retention of ATM at sites of DNA double 
      strand breaks. J Biol Chem 2001; 276: 38224-38230
28  Wright JA, Keegan KS, Herendeen DR, Bentley NJ, Carr AM, Hoekstra MF, Concannon P. Protein kinase mutants of 
      human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Proc Natl 
      Acad Sci U S A 1998; 95: 7445-7450
29  Hekmat-Nejad M, You Z, Yee MC, Newport JW, Cimprich KA. Xenopus ATR is a replication-dependent chromatin-
      binding protein required for the DNA replication checkpoint. Curr Biol 2000; 10: 1565-1573
30  Wahl GM, Carr AM. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature 
      Cell Biol 2001; 3: E227-E286
31  Suzuki K, Kodama S, Watanabe M. Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. 
      J Biol Chem 1999; 274: 25571-25575
32  Smith GC, Cary RB, Lakin ND, Hann BC, Teo SH, Chen DJ, Jackson SP. Purification and DNA binding properties of the
      ataxia-telangiectasia gene product ATM. Proc Natl Acad Sci U S A 1999; 96: 11134-11139
33  Guo Z, Kumagai A, Wang SX, Dunphy WG. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in
      response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev 2000; 14: 2745-2756
34  Unsal-Kacmaz K, Makhov AM, Griffith JD, Sancar A. Preferential binding of ATR protein to UV-damaged DNA. Proc Natl
      Acad Sci U S A 2002; 99: 6673-6678
35  Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in 
      the recognition and repair of aberrant DNA structures. Genes Dev 2000; 14: 927-939
36  Kim GD, Choi YH, Dimtchev A, Jeong SJ, Dritschilo A, Jung M. Sensing of ionizing radiation-induced DNA damage by 
      ATM through interaction with histone deacetylase. J Biol Chem 1999; 274: 31127-31130
37  Zou L, Cortez D, Elledge SJ. Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes 
      onto chromatin. Genes Dev 2002; 16: 198-208
38  Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT. Functional interactions between
      BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 2000; 14: 2989-3002
39  Schmidt DR, Schreiber SL. Molecular association between ATR and two components of the nucleosome remodeling 
      and deacetylating complex, HDAC2 and CHD4. Biochemistry 1999; 38: 14711-14717
40  Wang JY. Cellular responses to DNA damage. Curr Opin Cell Biol 1998; 10: 240-247
41  Wen ST, Van Etten RA. The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-
      binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev 1997; 11: 2456-2467
42  Kharbanda S, Ren R, Pandey P, Shafman TD, Feller SM, Weichselbaum RR, Kufe DW. Activation of the c-Abl tyrosine
      kinase in the stress response to DNA-damaging agents. Nature 1995; 376: 785-788
43  Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, Hobson K, Gatei M, Zhang N, Watters D, Egerton M, Shiloh 
      Y, Kharbanda S, Kufe D, Lavin MF. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 
      1997; 387: 520-523
44  Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y, Barlow C, Baltimore D, Wynshaw-Boris A, Kastan 
      MB, Wang JY. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. 
      Nature 1997; 387: 516-519
45  Shangary S, Brown KD, Adamson AW, Edmonson S, Ng B, Pandita TK, Yalowich J, Taccioli GE, Baskaran R. Regulation 
      of DNA-dependent protein kinase activity by ionizing radiation-activated Abl kinase is an ATM-dependent process. J 
      Biol Chem 2000; 275: 30163-30168
46  Takao N, Mori R, Kato H, Shinohara A, Yamamoto K. c-Abl tyrosine kinase is not essential for ataxia telangiectasia 
      mutated functions in chromosomal maintenance. J Biol Chem 2000; 275: 725-728
47  Yuan ZM, Huang Y, Whang Y, Sawyers C, Weichselbaum R, Kharbanda S, Kufe D. Role for c-Abl tyrosine kinase in 
      growth arrest response to DNA damage. Nature 1996; 382: 272-274
48  Wen ST, Jackson PK, van Etten RA. The cytostatic function of c-Abl is controlled by multiple nuclear localization signals 
      and requires the p53 and Rb tumor suppressor gene products. EMBO J 1996; 15: 1583-1595
49  Sionov RV, Moallem E, Berger M, Kazaz A, Gerlitz O, Ben-Neriah Y, Oren M, Haupt Y. C-Abl neutralizes the inhibitory 
      effect of Mdm2 on p53. J Biol Chem 1999; 274: 8371-8374
50  Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y, Ciechanover A, Haupt Y. C-Abl regulates p53 
      levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Mol Cell Biol 
      2001; 21: 5869-5878
51  Huang Y, Yuan ZM, Ishiko T, Nakada S, Utsugisawa T, Kato T, Kharbanda S, Kufe DW. Pro-apoptotic effect of the c-Abl
      tyrosine kinase in the cellular response to 1-beta-D-arabinofuranosylcytosine. Oncogene 1997; 15: 1947-1952
52  Yuan ZM, Huang Y, Ishiko T, Kharbanda S, Weichselbaum R, Kufe D. Regulation of DNA damage-induced apoptosis by 
      the c-Abl tyrosine kinase. Proc Natl Acad Sci U S A 1997; 94: 1437-1440
53  Shaul Y. C-Abl: activation and nuclear targets. Cell Death Differ 2000; 7: 10-16
54  Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, Wang JY. The tyrosine kinase c-Abl regulates p73 
      in apoptotic response to cisplatin-induced DNA damage. Nature 1999; 399: 806-809
55  Agami R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis.
      Nature 1999; 399: 809-813
56  Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD. Activation of the 
      ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998; 281: 1677-1679
57  Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y. 
      Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 1998; 281: 1674-1677
58  Nakagawa K, Taya Y, Tamai K, Yamaizumi M. Requirement of ATM in phosphorylation of the human p53 protein at 
      serine 15 following DNA double-strand breaks. Mol Cell Biol 1999; 19: 2828-2834
59  Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT. A role for 
      ATR in the DNA damage-induced phosphorylation of p53. Genes Dev 1999; 13: 152-157
60  Waterman MJ, Stavridi ES, Waterman JL, Halazonetis TD. ATM-dependent activation of p53 involves dephosphorylation
      and association with 14-3-3 proteins. Nat Genet 1998; 19: 175-178
61  Saito S, Goodarzi AA, Higashimoto Y, Noda Y, Lees-Miller SP, Appella E, Anderson CW. ATM mediates phosphorylation 
      at multiple p53 sites, including Ser(46), in response to ionizing radiation. J Biol Chem 2002; 277: 12491-12494
62  Alarcon-Vargas D, Ronai Z. p53-Mdm2-the affair that never ends. Carcinogenesis 2002; 23: 541-547
63  Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW. DNA damage-induced
      activation of p53 by the checkpoint kinase Chk2. Science 2000; 287: 1824-1827
64  Chehab NH, Malikzay A, Appel M, Halazonetis TD. Chk2/hCds1 functions as a DNA damage checkpoint in G1 by 
      stabilizing p53. Genes Dev 2000; 14: 278-288
65  Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD. Phosphorylation of Ser-20 mediates stabilization of human p53 in
      response to DNA damage. Proc Natl Acad Sci U S A 1999; 96: 13777-13782
66  Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D. Rapid ATM-dependent phosphorylation of MDM2 precedes
      p53 accumulation in response to DNA damage. Proc Natl Acad Sci U S A 1999; 96: 14973-14977
67  de Toledo SM, Azzam EI, Dahlberg WK, Gooding TB, Little JB. ATM complexes with HDM2 and promotes its rapid
      phosphorylation in a p53- independent manner in normal and tumor human cells exposed to ionizing radiation. 
      Oncogene 2000; 19: 6185-6193
68  Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, Moas M, Buschmann T, Ronai Z, Shiloh Y, Kastan MB, Katzir 
      E, Oren M. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes 
      Dev 2001; 15: 1067-1077
69  Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B, Kidd VJ, Mak TW, Ingram AJ. ERK activation mediates cell cycle 
      arrest and apoptosis after DNA damage independently of p53. J Biol Chem 2002; 277: 12710-12717
70  Zhang Y, Ma WY, Kaji A, Bode AM, Dong Z. Requirement of ATM in UVA-induced signaling and apoptosis. J Biol Chem
      2002; 277: 3124-3131
71  Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J. Involvement of the MKK6-p38g
      cascade in g-radiation-induced cell cycle arrest. Mol Cell Biol 2000; 20: 4543-4552
72  Sanchez-Prieto R, Sanchez-Arevalo VJ, Servitja JM, Gutkind JS. Regulation of p73 by c-Abl through the p38 MAP 
      kinase pathway. Oncogene 2002; 21: 974-979
73  Pandey P, Raingeaud J, Kaneki M, Weichselbaum R, Davis RJ, Kufe D, Kharbanda S. Activation of p38 mitogen-activated
      protein kinase by c-Abl-dependent and -independent mechanisms. J Biol Chem 1996; 271: 23775-23779
74  Cong F, Goff  SP. C-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 
      6 activation. Proc Natl Acad Sci U S A 1999; 96: 13819-13824
75  Ito Y, Pandey P, Sathyanarayana P, Ling P, Rana A, Weichselbaum R, Tan TH, Kufe D, Kharbanda S. Interaction of
      hematopoietic progenitor kinase 1 and c-Abl tyrosine kinase in response to genotoxic stress. J Biol Chem 
      2001; 276: 18130-18138
76  Liu RY, Fan C, Liu G, Olashaw NE, Zuckerman KS. Activation of p38 mitogen-activated protein kinase is required for 
      tumor necrosis factor-a-supported proliferation of leukemia and lymphoma cell lines. J Biol Chem 
      2000; 275: 21086-21093
77  Bar-Shira A, Rashi-Elkeles S, Zlochover L, Moyal L, Smorodinsky NI, Seger R, Shiloh Y. ATM-dependent activation of 
      the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage. Oncogene 2002; 21: 849-855
78  Ejima Y, Yang L, Sasaki MS. Aberrant splicing of the ATM gene associated with shortening of the intronic 
      mononucleotide tract in human colon tumor cell lines: a novel mutation target of microsatellite instability. 
      Int J Cancer 2000; 86: 262-268
79  Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW. Genome-wide search for loss of
      heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator 
      phenotype and breast cancer pathogenesis. Cancer Res 2000; 60: 3884-3892
80  Worgul BV, Smilenov L, Brenner DJ, Junk A, Zhou W, Hall EJ. Atm heterozygous mice are more sensitive to
      radiation-induced cataracts than are their wild-type counterparts. Proc Natl Acad Sci U S A 2002; 99: 9836-9839
81  Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, Ramsay J, McKinnon PJ, Swift M, Lavin 
      MF. Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility 
      to cancer. Nat Genet 2002; 32: 185-190
82  Concannon P. ATM heterozygosity and cancer risk. Nat Genet 2002; 32: 89-90
83  Brown EJ, Baltimore D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes 
      Dev 2000; 14: 397-402
84  de Klein A, Muijtjens M, van Os R, Verhoeven Y, Smit B, Carr AM, Lehmann AR, Hoeijmakers JH. Targeted disruption 
      of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr Biol 2000; 10: 479-482
85  Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH. Overexpression of a kinase-
      inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J 
      1998; 17: 159-169
86  Smith GC, d'Adda di Fagagna F, Lakin ND, Jackson SP. Cleavage and inactivation of ATM during apoptosis. Mol Cell 
      Biol 1999; 19: 6076-6084
87  Hotti A, Jarvinen K, Siivola P, Holtta E. Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as 
      a new target of caspases. Oncogene 2000; 19: 2354-2362
88  Tong X, Liu B, Dong Y, Sun Z. Cleavage of ATM during radiation-induced apoptosis: caspase-3-like apoptotic protease 
      as a candidate. Int J Radiat Biol 2000; 76: 1387-1395
89  Cortez D, Guntuku S, Qin J, Elledge SJ. ATR and ATRIP: partners in checkpoint signaling. Science 2001;294:1713-1716
90  Williams GM, Weisburger JH. Chemical Carcinogenesis. New York, NY, Pergamon Press 1991
91  Smart RC. Carcinogenesis. Norwalk, CT, Appleton Lange 1994
92  Yang J, Yu Y, Hamrick HE, Duerksen-Hughes PJ. ATM, ATR, and DNA-PK: initiators of the cellular genotoxic stress
      responses. Carcinogenesis 2003; 24: 1571-1580

   Edited by Zhu LH and Wang XL   

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