DNA damage tumor suppressor genes and genomic instability
Introduction
Environmental insults, including ultraviolet light, ionizing radiation (IR), and oxidative stress, such as that attributable to reactive oxygen species derived from oxidative metabolism, continually damage the genome of cells. In dividing cells, it is also prone to the introduction of errors during DNA replication and mitosis. Organisms have evolved mechanisms that maintain genomic integrity by inducing cell cycle arrest in response to DNA damage. Such checkpoint mechanisms allow the cell time to repair the DNA damage before cell cycle progression is resumed, or, if the damage is too extensive, they trigger apoptosis or cellular senescence. Defective checkpoint responses can thus result in genomic instability and lead to the transformation of normal cells into cancer cells. In familial cancer syndromes such as ataxia telangiectasia (AT), AT-like disorder, Li–Fraumeni syndrome, Nijmegen breakage syndrome (NBS), Fanconi anemia, and hereditary breast cancer, the mutated genes are involved in cell-cycle checkpoints or repair of DNA damage. Both ATM (AT mutated) and ATR (ATM- and Rad3-related) are members of the phosphatidylinositol 3-kinase–related kinase (PIKK) family of protein kinases and regulate a large number of proteins, including the kinases Chk1 and Chk2, that function in checkpoints activated during G1, S, or G2 phases of the cell cycle in response to DNA damage [1]. Here we review recent progress in the characterization of cell-cycle checkpoint mechanisms mediated by ATM, ATR, and their downstream targets Chk1 and Chk2 as well as insight gained into the roles of these mechanisms in DNA repair, the induction of apoptosis or senescence, and tumor suppression.
Section snippets
Sensing and signaling DNA damage
ATM and ATR trigger diverse cellular responses to DNA damage or stalled DNA replication during activation of the G1–S, intra-S, or G2 checkpoints [1]. ATM is encoded by the gene that is mutated in individuals with AT, which is characterized by progressive neurological degeneration, telangiectasia, growth retardation, specific immunodeficiency, a high sensitivity to IR, and an increased incidence of malignancy. A splicing mutation of the ATR gene has been identified in individuals with Seckel
The G1–S checkpoint: role of an ATM–Chk2–p53 pathway
The most fundamental event in the G1–S checkpoint is the stabilization and activation of p53, which, in turn, induces transcription of the gene for p21, an inhibitor of the cyclin E–CDK2 complex. Signals that regulate p53 ultimately converge to disrupt the interaction between p53 and its negative regulator MDM2. The MDM2 oncoprotein is a RING-finger-type ubiquitin ligase that ubiquitinates both itself and p53; its binding to the N-terminus of p53 thus results in the ubiquitination of p53 and
The intra-S checkpoint: role of ATM-mediated pathways
Radio-resistant DNA synthesis is a phenotypic hallmark of cells derived from individuals with AT, AT-like disorder, Fanconi anemia, or NBS, indicating that the proteins encoded by the genes that are mutated in these various disorders play a role in the intra–S phase checkpoint. Two pathways that have been implicated in activation of the intra-S checkpoint are those mediated by ATM–Chk2–CDC25A and by ATM–NBS1–SMC1 [24].
CDC25A is a phosphatase that activates CDK2 by dephosphorylation at Thr-14
The G2 checkpoint: roles of ATM and ATR
The central event in activation of the G2 checkpoint is inhibition of the mitosis-promoting phosphatase CDC25C. Studies of (embryonic) cells deficient in ATM, ATR, or Chk1 have shown that the ATM/ATR–Chk1 pathway is responsible for activation of the G2 checkpoint in response to DNA damage induced by IR [29•]. ATR and ATM each activate Chk1 by phosphorylation on Ser-317 and Ser-345, and activated Chk1 phosphorylates CDC25C on Ser-217 and thereby creates a binding site for 14-3-3 protein. Its
Apoptosis induction and tumor suppression
Cells that experience a level of DNA damage beyond repair either enter senescence or undergo apoptosis to prevent the propagation of carcinogenic genetic alterations. The p53 tumor suppressor protein plays a central role in the decision of a cell to undergo apoptosis after exposure to diverse stresses, including DNA damage. As described above, Chk2 is an important regulator of both the stability and the trans-activation activity of p53 in cells exposed to IR 21.••, 22.••. Activation of Chk2
Cooperation of cell-cycle checkpoints and DNA repair in tumor suppression
Mice that lack either ATM or 53BP1 [10], both of which are upstream mediators of the DNA-damage response and participate in both cell-cycle checkpoint and DNA-repair pathways, are predisposed to the development of cancer. The contributions of defective DNA repair and impaired checkpoint function to tumor development have been investigated with mice that are deficient in both p53 and proteins important in the nonhomologous end joining (NHEJ) pathway of DNA repair, such as Xrcc4, DNA ligase IV,
Conclusions
We have provided an overview of recent advances in the characterization of cell-cycle checkpoints and their roles in facilitation of the repair of DNA damage and tumor suppression (Figure 1). The increased genomic instability apparent in cancer cells reflects the fact that the accumulation of genetic mutations as a result of defects in cell-cycle checkpoints or DNA repair activity is an important cause of tumorigenesis. Given that mutations in the genes for various proteins that contribute to
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
We thank Hiroyuki Takai and members of our laboratory for stimulating discussions. Research in the authors’ laboratory was supported by Grant-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan.
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