The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

Falck, Jacob; Mailand, Niels; Syljuåsen, Randi G.; Bártek, Jiří; Lukáš, Jiří

doi:10.1038/35071124

Cited by 959 publications

(933 citation statements)

References 30 publications

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“…Interestingly, we repeatedly observed that the rate of DNA synthesis increased slightly at low dose(s) of irradiation in p53À/À and ATMÀ/À MEFs. This slight increase was consistent with that reported in cells from A-T patients (Falck et al, 2001). The low-dose-specific RDS in p53À/À MEFs was not owing to abrogation of a p53/p21 regulated G1/S-phase checkpoint in the cells, as suppression of DNA synthesis in p21À/À MEFs exhibited the same low-dose-specific sharp decrease as in WT MEFs in addition to the high-dose range moderate decrease (Figure 1a).…”

Section: Resultssupporting

confidence: 90%

“…The low-dose component operates at doses below 2.5 Gy and is dependent on the functional p53. p53 was reported not to be required in the S-phase DNA damage checkpoint (Xie et al, 1998;Falck et al, 2001;Merrick et al, 2004). However, these studies used gamma-ray doses higher than 5 Gy, which are supra-lethal to the cells.…”

Section: Discussionmentioning

confidence: 99%

“…Suppression of replication fork progression was demonstrated in a classic work of fiber autoradiography analysis of irradiated cells (Watanabe, 1974). As p53 was reported not to be required for the suppression of origin firing (Xie et al, 1998;Falck et al, 2001;Merrick et al, 2004), the p53-dependent S-phase DNA damage checkpoint is likely to act by suppressing replication fork progression.…”

Section: Introductionmentioning

confidence: 99%

“…Suppression of late origin firing in response to DNA damage is dependent on Mec1 and Rad53 in yeast (Santocanale and Diffley, 1998;Shirahige et al, 1998), and on their respective homologues ATM and Chk2 in mammalian cells (Larner et al, 1999;Falck et al, 2001). Suppression of replication fork progression was demonstrated in a classic work of fiber autoradiography analysis of irradiated cells (Watanabe, 1974).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53À/À MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis revealed that 1 Gy irradiation suppressed replication fork progression in p53 WT MEFs, but not in p53À/À MEFs. Proliferating cell nuclear antigen (PCNA), clamp loader of DNA polymerase, was phosphorylated in WT MEFs after 1 Gy irradiation and redistributed to form foci in the nuclei. In contrast, PCNA was not phosphorylated and dissociated from chromatin in 1 Gy-irradiated p53À/À MEFs. These results demonstrate that the novel low-dosespecific p53-dependent S-phase DNA damage checkpoint is likely to regulate the replication fork movement through phosphorylation of PCNA.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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“…Two of the variants, a missense variant 470T4C (I157T) in exon 3 and a frameshift mutation 1100delC in exon 10, were the same as previously reported in patients with Li -Fraumeni syndrome (Bell et al, 1999), breast (Allinen et al, 2001;Vahteristo et al, 2002), and prostate cancer (Dong et al, 2003). The frameshift 1100delC mutation has been proven to result in the loss of kinase activity (Wu et al, 2001), and I157T variant has been shown to be defective in its ability to bind and phosphorylate Cdc25A, one of its normal substrates (Falck et al, 2001). These variants were further studied in a set of 1137 samples.…”

Section: Resultssupporting

confidence: 62%

CHEK2 variants associate with hereditary prostate cancer

et al. 2003

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Recently, variants in CHEK2 gene were shown to associate with sporadic prostate cancer in the USA. In the present study from Finland, we found that the frequency of 1100delC, a truncating variant that abrogates the kinase activity, was significantly elevated among 120 patients with hereditary prostate cancer (HPC) (four out of 120 (3.3%); odds ratio 8.24; 95% confidence interval 1.49 -45.54; P ¼ 0.02) compared to 480 population controls. Suggestive evidence of segregation between the 1100delC mutation and prostate cancer was seen in all positive families. In addition, I157T variant had significantly higher frequency among HPC patients (13 out of 120 (10.8%); odds ratio 2.12; 95% confidence interval 1.06 -4.27; P ¼ 0.04) than the frequency 5.4% seen in the population controls. The results suggest that CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level.

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Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors

et al. 2019

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; for the Regeneron Genetics Center (RGC) Research Team IMPORTANCE Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. OBJECTIVE To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. DESIGN, SETTING, AND PARTICIPANTS A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. MAIN OUTCOMES AND MEASURES Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. RESULTS Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). CONCLUSIONS AND RELEVANCE This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

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The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

Cited by 959 publications

References 30 publications

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

CHEK2 variants associate with hereditary prostate cancer

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors

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