The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
Abstract
When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.
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Chk1 and Chk2 control functional associations among BRCA1, BRCA2, and Rad51 after DNA damage, promoting HR-mediated repair of stalled replication forks.
“Both Chk1 and Chk2 regulate the functional associations between BRCA1, BRCA2, and Rad51 proteins in response to DNA damage, and thus promote HR-mediated repair of stalled replication forks [27, 28].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [28]
Both the ATR-Chk1 and ATM-Chk2 pathways regulate HR-mediated repair of collapsed replication forks.
“Moreover, both the ATR-Chk1 and ATM-Chk2 pathways regulate HR-mediated repair of collapsed replication forks [27, 28].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [28]
Spontaneous HR is promoted by collapsed replication forks caused by endogenous DNA single-strand breaks.
“It has been established that spontaneous HR is promoted by collapsed replication forks that are caused by endogenous DNA SSB [24, 28].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [28]
Cites
Hartwell, L. H., & Kastan, M. B. (1994) · Science · doi:10.1126/science.7997877 · Cited by 2,523 · see citing works
Cell Cycle Checkpoints: Preventing an Identity Crisis
Elledge, S. J. (1996) · Science · doi:10.1126/science.274.5293.1664 · Cited by 2,047 · see citing works
Peng, C.-Y., Graves, P. R., Thoma, R. S., Wu, Z., Shaw, A. S., & Piwnica-Worms, H. (1997) · Science · doi:10.1126/science.277.5331.1501 · Cited by 1,341 · see citing works
Linkage of ATM to Cell Cycle Regulation by the Chk2 Protein Kinase
Matsuoka, S. (1998) · Science · doi:10.1126/science.282.5395.1893 · Cited by 1,322 · see citing works
Sanchez, Y., Wong, C., Thoma, R. S., Richman, R., Wu, Z., Piwnica-Worms, H., & Elledge, S. J. (1997) · Science · doi:10.1126/science.277.5331.1497 · Cited by 1,320 · see citing works
The complexity of p53 modulation: emerging patterns from divergent signalsPreprint
Giaccia, A. J., & Kastan, M. B. (1998) · Genes & Development · doi:10.1101/gad.12.19.2973 · Cited by 1,303 · see citing works
DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2
Hirao, A., Kong, Y., Matsuoka, S., Wakeham, A. C., Ruland, J., Yoshida, H., Liu, D., Elledge, S. J., & Mak, T. W. (2000) · Science · doi:10.1126/science.287.5459.1824 · Cited by 1,288 · see citing works
Stewart, G. S., Maser, R. S., Stankovic, T., Bressan, D. A., Kaplan, M. I., Jaspers, N. G. J., Raams, A., Byrd, P. J., Petrini, J. H. J., & Taylor, A. M. R. (1999) · Cell · doi:10.1016/s0092-8674(00)81547-0 · Cited by 1,060 · see citing works
Heterozygous Germ Line hCHK2 Mutations in Li-Fraumeni Syndrome
Bell, D. W., Varley, J. M., Szydlo, T. E., Kang, D. H., Wahrer, D. C. R., Shannon, K. E., Lubratovich, M. L., Verselis, S. J., Isselbacher, K. J., Fraumeni, J. F., et al. (1999) · Science · doi:10.1126/science.286.5449.2528 · Cited by 899 · see citing works
14-3-3σ is required to prevent mitotic catastrophe after DNA damage
Chan, T. A., Hermeking, H., Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1999) · Nature · doi:10.1038/44188 · Cited by 895 · see citing works
Chk2/hCds1 functions as a DNA damage checkpoint in G<sub>1</sub>by stabilizing p53
Chehab, N. H., Malikzay, A., Appel, M., & Halazonetis, T. D. (2000) · Genes & Development · doi:10.1101/gad.14.3.278 · Cited by 805 · see citing works
Radiosensitivity in ataxia-telangiectasia: a new explanation.
Painter, R. B., & Young, B. R. (1980) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.77.12.7315 · Cited by 794 · see citing works
Rapid Destruction of Human Cdc25A in Response to DNA Damage
Mailand, N., Falck, J., Lukas, C., Syljuåsen, R. G., Welcker, M., Bartek, J., & Lukas, J. (2000) · Science · doi:10.1126/science.288.5470.1425 · Cited by 787 · see citing works
Self-citationATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
Lim, D.-S., Kim, S.-T., Xu, B., Maser, R. S., Lin, J., Petrini, J. H. J., & Kastan, M. B. (2000) · Nature · doi:10.1038/35007091 · Cited by 786 · see citing works
Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15.
Gu, Y., Rosenblatt, J., & Morgan, D. O. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05493.x · Cited by 648 · see citing works
Cdc25 Mitotic Inducer Targeted by Chk1 DNA Damage Checkpoint Kinase
Furnari, B. A., Rhind, N., & Russell, P. R. (1997) · Science · doi:10.1126/science.277.5331.1495 · Cited by 542 · see citing works
hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response
Lee, J., Collins, K. M., Brown, A. L., Lee, C. H., & Chung, J. H. (2000) · Nature · doi:10.1038/35004614 · Cited by 529 · see citing works
Galaktionov, K. I., & Beach, D. (1991) · Cell · doi:10.1016/0092-8674(91)90294-9 · Cited by 511 · see citing works
CDC25 Phosphatases as Potential Human Oncogenes
Galaktionov, K. I., Lee, A. K., Eckstein, J., Draetta, G. F., Meckler, J., Loda, M. F., & Beach, D. (1995) · Science · doi:10.1126/science.7667636 · Cited by 502 · see citing works
Hoffmann, I., Draetta, G. F., & Karsenti, E. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06750.x · Cited by 495 · see citing works
Cdc25A is a novel phosphatase functioning early in the cell cycle.
Jinno, S., Suto, K., Nagata, A., Igarashi, M., Kanaoka, Y., Nojima, H., & Okayama, H. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06417.x · Cited by 452 · see citing works
Rad53 FHA Domain Associated with Phosphorylated Rad9 in the DNA Damage Checkpoint
Sun, Z., Hsiao, J., Fay, D. S., & Stern, D. F. (1998) · Science · doi:10.1126/science.281.5374.272 · Cited by 398 · see citing works
The FHA Domain Is a Modular Phosphopeptide Recognition Motif
Durocher, D., Henckel, J., Fersht, A. R., & Jackson, S. P. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80340-8 · Cited by 396 · see citing works
Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1
Zeng, Y., Forbes, K. C., Wu, Z., Moreno, S., Piwnica-Worms, H. M., & Enoch, T. (1998) · Nature · doi:10.1038/26766 · Cited by 341 · see citing works
Replication Checkpoint Enforced by Kinases Cds1 and Chk1
Boddy, M. N., Furnari, B., Mondesert, O., & Russell, P. (1998) · Science · doi:10.1126/science.280.5365.909 · Cited by 316 · see citing works
ATM: A mediator of multiple responses to genotoxic stress
Rotman, G., & Shiloh, Y. (1999) · Oncogene · doi:10.1038/sj.onc.1203124 · Cited by 272 · see citing works
DNA Damage and Checkpoint Pathways
Weinert, T. A. (1998) · Cell · doi:10.1016/s0092-8674(00)81597-4 · Cited by 253 · see citing works
Molinari, M., Mercurio, C., Dominguez, J., Goubin, F., & Draetta, G. F. (2000) · EMBO Reports · doi:10.1093/embo-reports/kvd018 · Cited by 203 · see citing works
Involvement of Myc Activity in a G 1 /S-Promoting Mechanism Parallel to the pRb/E2F Pathway
Santoni‐Rugiu, E., Falck, J., Mailand, N., Bártek, J., & Lukas, J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.10.3497-3509.2000 · Cited by 172 · see citing works
Self-citationRequirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints
Xie, G., Habbersett, R. C., Jia, Y., Peterson, S., Lehnert, B. E., Bradbury, E. M., & D'Anna, J. A. (1998) · Oncogene · doi:10.1038/sj.onc.1201793 · Cited by 61 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073723 · Cited by 3,317 · see citing works
ATM and related protein kinases: safeguarding genome integrity
Shiloh, Y. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1011 · Cited by 2,577 · see citing works
Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966 · see citing works
DNA repair pathways as targets for cancer therapy
Helleday, T., Petermann, E., Lundin, C., Hodgson, B., & Sharma, R. A. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2342 · Cited by 1,666 · see citing works
Chk1 and Chk2 kinases in checkpoint control and cancer
Bartek, J., & Lukas, J. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00110-7 · Cited by 1,513 · see citing works
Self-citationCell death by mitotic catastrophe: a molecular definition
Castedo, M., Perfettini, J.-L., Roumier, T., Andreau, K., Medema, R., & Kroemer, G. (2004) · Oncogene · doi:10.1038/sj.onc.1207528 · Cited by 1,269 · see citing works
BRCA1 and BRCA2: 1994 and beyond
Narod, S. A., & Foulkes, W. D. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1431 · Cited by 967 · see citing works
Regulation of Ligands for the NKG2D Activating Receptor
Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W., & Jung, H. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095951 · Cited by 850 · see citing works
Targeting the Cell Cycle: A New Approach to Cancer Therapy
Schwartz, G. K., & Shah, M. A. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.5594 · Cited by 816 · see citing works
Toward Maintaining the Genome: DNA Damage and Replication Checkpoints
Nyberg, K. A., Michelson, R. J., Putnam, C. W., & Weinert, T. A. (2002) · Annual Review of Genetics · doi:10.1146/annurev.genet.36.060402.113540 · Cited by 770 · see citing works
Checking on DNA damage in S phase
Bartek, J., Lukas, C., & Lukas, J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1493 · Cited by 758 · see citing works
Self-citationCDC25 phosphatases in cancer cells: key players? Good targets?
Boutros, R., Lobjois, V., & Ducommun, B. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2169 · Cited by 710 · see citing works
ATM and ATR as therapeutic targets in cancer
Weber, A. M., & Ryan, A. J. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.12.001 · Cited by 644 · see citing works
DNA double-strand break repair: From mechanistic understanding to cancer treatment
HELLEDAY, T., LO, J., VANGENT, D., & ENGELWARD, B. (2007) · DNA Repair · doi:10.1016/j.dnarep.2007.02.006 · Cited by 640 · see citing works
Murr, R., Loizou, J. I., Yang, Y.-G., Cuenin, C., Li, H., Wang, Z.-Q., & Herceg, Z. (2006) · Nature Cell Biology · doi:10.1038/ncb1343 · Cited by 613 · see citing works
Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damagePreprint
Kim, S., Xu, B., & Kastan, M. B. (2002) · Genes & Development · doi:10.1101/gad.970602 · Cited by 581 · see citing works
Mammalian G1- and S-phase checkpoints in response to DNA damage
Bártek, J., & Lukas, J. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00280-5 · Cited by 573 · see citing works
Self-citationHydrogen peroxide – production, fate and role in redox signaling of tumor cells
Lennicke, C., Rahn, J., Lichtenfels, R., Wessjohann, L. A., & Seliger, B. (2015) · Cell Communication and Signaling · doi:10.1186/s12964-015-0118-6 · Cited by 572 · see citing works
Regulation and mechanisms of mammalian double-strand break repair
Valerie, K. C., & Povirk, L. F. (2003) · Oncogene · doi:10.1038/sj.onc.1206679 · Cited by 572 · see citing works
Sørensen, C. S., Syljuåsen, R. G., Falck, J., Schroeder, T., Rönnstrand, L., Khanna, K. K., Zhou, B.-B., Bártek, J., & Lukas, J. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00048-5 · Cited by 560 · see citing works
Self-citationThe decision to enter mitosis: feedback and redundancy in the mitotic entry network
Lindqvist, A., Rodríguez-Bravo, V., & Medema, R. H. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200812045 · Cited by 559 · see citing works
CHEK2 Is a Multiorgan Cancer Susceptibility Gene
Cybulski, C., Górski, B., Huzarski, T., Masojć, B., Mierzejewski, M., Dębniak, T., Teodorczyk, U., Byrski, T., Gronwald, J., Matyjasik, J., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/426403 · Cited by 548 · see citing works
Patsoukis, N., Brown, J., Petkova, V., Liu, F., Li, L., & Boussiotis, V. A. (2012) · Science Signaling · doi:10.1126/scisignal.2002796 · Cited by 529 · see citing works
DNA Methyltransferases, DNA Damage Repair, and Cancer
Jin, B., & Robertson, K. D. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-9967-2_1 · Cited by 521 · see citing works
MDC1 is required for the intra-S-phase DNA damage checkpoint
Goldberg, M., Stucki, M., Falck, J., D'Amours, D., Rahman, D., Pappin, D., Bartek, J., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature01445 · Cited by 506 · see citing works
Self-citationSMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpointPreprint
Yazdi, P. T., Wang, Y., Zhao, S., Patel, N., Lee, E. Y.-H. P., & Qin, J. (2002) · Genes & Development · doi:10.1101/gad.970702 · Cited by 505 · see citing works
Fei, P., & El‐Deiry, W. S. (2003) · Oncogene · doi:10.1038/sj.onc.1206677 · Cited by 497 · see citing works
Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2
Reinhardt, H. C., & Yaffe, M. B. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.01.018 · Cited by 494 · see citing works
Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage.
Lukas, C., Falck, J., Bartkova, J., Bartek, J., & Lukas, J. (2003) · Nature Cell Biology · doi:10.1038/ncb945 · Cited by 474 · see citing works
Self-citationDNA damage checkpoint control in cells exposed to ionizing radiation
Iliakis, G. E., Wang, Y., Guan, J., & Wang, H. (2003) · Oncogene · doi:10.1038/sj.onc.1206682 · Cited by 474 · see citing works
CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair
Esashi, F., Christ, N., Gannon, J., Liu, Y., Hunt, T., Jasin, M., & West, S. C. (2005) · Nature · doi:10.1038/nature03404 · Cited by 473 · see citing works
Two Molecularly Distinct G2/M Checkpoints Are Induced by Ionizing Irradiation
Xu, B., Kim, S., Lim, D., & Kastan, M. B. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.4.1049-1059.2002 · Cited by 470 · see citing works
* (2004) · The American Journal of Human Genetics · doi:10.1086/421251 · Cited by 466 · see citing works
Roles of Chk1 in cell biology and cancer therapy
Zhang, Y., & Hunter, T. (2014) · International Journal of Cancer · doi:10.1002/ijc.28226 · Cited by 462 · see citing works
Zhao, H., Watkins, J. L., & Piwnica-Worms, H. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182557299 · Cited by 459 · see citing works
CHK2 kinase in the DNA damage response and beyond
Zannini, L., Delia, D., & Buscemi, G. (2014) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mju045 · Cited by 455 · see citing works
Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage
Busino, L., Donzelli, M., Chiesa, M., Guardavaccaro, D., Ganoth, D., Valerio Dorrello, N., Hershko, A., Pagano, M., & Draetta, G. F. (2003) · Nature · doi:10.1038/nature02082 · Cited by 447 · see citing works
Convergence of the Fanconi Anemia and Ataxia Telangiectasia Signaling Pathways
Taniguchi, T., García-Higuera, I., Xu, B., Andreassen, P. R., Gregory, R. C., Kim, S., Lane, W. S., Kastan, M. B., & D’Andrea, A. D. (2002) · Cell · doi:10.1016/s0092-8674(02)00747-x · Cited by 447 · see citing works
Regulating mammalian checkpoints through Cdc25 inactivation
Donzelli, M., & Draetta, G. F. (2003) · EMBO Reports · doi:10.1038/sj.embor.embor887 · Cited by 435 · see citing works
DNA damage checkpoints in mammals
Niida, H., & Nakanishi, M. (2005) · Mutagenesis · doi:10.1093/mutage/gei063 · Cited by 431 · see citing works
Durocher, D., & Jackson, S. P. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03294-x · Cited by 421 · see citing works
The when and wheres of CDC25 phosphatases
Boutros, R., Dozier, C., & Ducommun, B. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.02.003 · Cited by 417 · see citing works
Imidazoles as potential anticancer agents
Ali, I., Lone, M. N., & Aboul‐Enein, H. Y. (2017) · MedChemComm · doi:10.1039/c7md00067g · Cited by 413 · see citing works
Hirao, A., Cheung, A., Duncan, G. S., Girard, P.-M., Elia, A., Wakeham, A. C., Okada, H., Sarkissian, T., Wong, J. A., Sakai, T., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.18.6521-6532.2002 · Cited by 404 · see citing works
Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.
Kondapaka, S. B., Singh, S. S., Dasmahapatra, G. P., Sausville, E. A., & Roy, K. K. (2003) · PubMed · Cited by 402 · see citing works
Chk2 kinase — a busy messenger
Bártek, J., Falck, J., & Lukas, J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35103059 · Cited by 400 · see citing works
Self-citationDiTullio, R. A., Mochan, T. A., Venere, M., Bártková, J., Sehested, M., Bártek, J., & Halazonetis, T. D. (2002) · Nature Cell Biology · doi:10.1038/ncb892 · Cited by 399 · see citing works
The DNA damage-dependent intra–S phase checkpoint is regulated by parallel pathways
Falck, J., Petrini, J. H. J., Williams, B. R., Lukas, J., & Bartek, J. (2002) · Nature Genetics · doi:10.1038/ng845 · Cited by 392 · see citing works
Self-citationTargeting the checkpoint kinases: chemosensitization versus chemoprotection
Zhou, B. S., & Bártek, J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1296 · Cited by 390 · see citing works
Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents
Xiao, Z., Chen, Z., Gunasekera, A. H., Sowin, T. J., Rosenberg, S. H., Fesik, S., & Zhang, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300229200 · Cited by 388 · see citing works
Chk2 activates E2F-1 in response to DNA damage
Stevens, C., Smith, L. M., & Thangue, N. B. L. (2003) · Nature Cell Biology · doi:10.1038/ncb974 · Cited by 386 · see citing works
Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time
Lukas, J., Lukas, C., & Bartek, J. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.006 · Cited by 381 · see citing works
Self-citationG2 checkpoint abrogators as anticancer drugs
Kawabe, T. (2004) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.513.3.4 · Cited by 376 · see citing works
Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword
Visconti, R., Monica, R. D., & Grieco, D. (2016) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-016-0433-9 · Cited by 364 · see citing works
Anticancer Activity of Chitosan, Chitosan Derivatives, and Their Mechanism of Action
Adhikari, H. S., & Yadav, P. N. (2018) · International Journal of Biomaterials · doi:10.1155/2018/2952085 · Cited by 364 · see citing works
An ATR- and Cdc7-Dependent DNA Damage Checkpoint that Inhibits Initiation of DNA Replication
Costanzo, V., Shechter, D., Lupardus, P. J., Cimprich, K. A., Gottesman, M. E., & Gautier, J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(02)00799-2 · Cited by 355 · see citing works
SCF<sup>β-TRCP</sup> links Chk1 signaling to degradation of the Cdc25A protein phosphatase
Jin, J., Shirogane, T., Xu, L., Nalepa, G., Qin, J., Elledge, S. J., & Harper, J. W. (2003) · Genes & Development · doi:10.1101/gad.1157503 · Cited by 340 · see citing works
CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage
Huang, H., Regan, K. M., Lou, Z., Chen, J., & Tindall, D. J. (2006) · Science · doi:10.1126/science.1130512 · Cited by 334 · see citing works
MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways
Lou, Z., Minter‐Dykhouse, K., Wu, X., & Chen, J. (2003) · Nature · doi:10.1038/nature01447 · Cited by 328 · see citing works
Activation of mammalian Chk1 during DNA replication arrest
Feijóo, C. G., Hall-Jackson, C. A., Wu, R., Jenkins, D., Leitch, J., Gilbert, D. M., & Smythe, C. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200104099 · Cited by 318 · see citing works
Durant, S. T., Zheng, L., Wang, Y., Chen, K., Zhang, L., Zhang, T., Yang, Z., Riches, L. C., Trinidad, A. G., Fok, J. H. L., et al. (2018) · Science Advances · doi:10.1126/sciadv.aat1719 · Cited by 316 · see citing works
Regulation of G2/M events by Cdc25A through phosphorylation‐dependent modulation of its stability
Mailand, N., Podtelejnikov, A. V., Groth, A., Mann, M., Bartek, J., & Lukas, J. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf567 · Cited by 315 · see citing works
Self-citationChk1 promotes replication fork progression by controlling replication initiation
Petermann, E., Woodcock, M., & Helleday, T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005031107 · Cited by 308 · see citing works
Mutations in CHEK2 Associated with Prostate Cancer Risk
Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J. M., McDonnell, S. K., Qian, C., Marks, A. F., Slager, S. L., Peterson, B. J., et al. (2003) · The American Journal of Human Genetics · doi:10.1086/346094 · Cited by 306 · see citing works
Exploiting replicative stress to treat cancer
Dobbelstein, M., & Sørensen, C. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4553 · Cited by 300 · see citing works
Right Place, Right Time, and Only Once: Replication Initiation in Metazoans
Machida, Y., Hamlin, J. L., & Dutta, A. (2005) · Cell · doi:10.1016/j.cell.2005.09.019 · Cited by 293 · see citing works
Lage, K., Hansen, N. T., Karlberg, E. O., Eklund, A. C., Roque, F. S., Donahoe, P. K., Szallasi, Z., Jensen, T. S., & Brunak, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810772105 · Cited by 292 · see citing works
The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle
Shaltiël, I. A., Krenning, L., Bruinsma, W., & Medema, R. H. (2015) · Journal of Cell Science · doi:10.1242/jcs.163766 · Cited by 289 · see citing works
CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin?
Antoni, L., Sodha, N., Collins, I., & Garrett, M. D. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2251 · Cited by 287 · see citing works
ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses
Yang, H. J. (2003) · Carcinogenesis · doi:10.1093/carcin/bgg137 · Cited by 275 · see citing works
Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation
Zegerman, P., & Diffley, J. F. X. (2010) · Nature · doi:10.1038/nature09373 · Cited by 273 · see citing works
Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics
Ma, C. X., Janetka, J. W., & Piwnica-Worms, H. M. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.10.009 · Cited by 271 · see citing works
Zhang, B., Beeghly-Fadiel, A. C., Long, J., & Zheng, W. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70076-6 · Cited by 270 · see citing works
Stracker, T. H., Theunissen, J.-W. F., Morales, M., & Petrini, J. H. J. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.014 · Cited by 263 · see citing works
Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities
He, G., Siddik, Z. H., Huang, Z.-F., Wang, R., Koomen, J. M., Kobayashi, R., Khokhar, A. R., & Kuang, J. (2005) · Oncogene · doi:10.1038/sj.onc.1208474 · Cited by 262 · see citing works
Mailand, N., Bekker-Jensen, S., Bartek, J., & Lukas, J. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.06.016 · Cited by 258 · see citing works
Self-citationDNA Damage Signaling and p53-dependent Senescence after Prolonged β-Interferon Stimulation
Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A., & Ferbeyre, G. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-09-0858 · Cited by 252 · see citing works
Heffernan, T. P., Simpson, D. A., Frank, A. R., Heinloth, A. N., Paules, R. S., Cordeiro-Stone, M., & Kaufmann, W. K. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.24.8552-8561.2002 · Cited by 251 · see citing works
Hong, Y., & Stambrook, P. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401346101 · Cited by 248 · see citing works
Stojic, L., Mojas, N., Cejka, P., di Pietro, M., Ferrari, S., Marra, G., & Jiricny, J. (2004) · Genes & Development · doi:10.1101/gad.294404 · Cited by 246 · see citing works
Adaptation to P Element Transposon Invasion in Drosophila melanogaster
Khurana, J. S., Wang, J., Xu, J. L., Koppetsch, B. S., Thomson, T., Nowosielska, A., Li, C., Zamore, P. D., Weng, Z., & Theurkauf, W. E. (2011) · Cell · doi:10.1016/j.cell.2011.11.042 · Cited by 246 · see citing works
Tan, Y., Raychaudhuri, P., & Costa, R. H. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01068-06 · Cited by 245 · see citing works
Development of Cell-Cycle Inhibitors for Cancer Therapy
Dickson, M. A., & Schwartz, G. K. (2009) · Current Oncology · doi:10.3747/co.v16i2.428 · Cited by 243 · see citing works
Wang, G., Li, X., Huang, F., Zhao, J., Ding, H., Cunningham, C., Coad, J. E., Flynn, D. C., Reed, E., & Li, Q. Q. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5017-3 · Cited by 242 · see citing works
Ünsal-Kaçmaz, K., Chastain, P. D., Qu, P.-P., Minoo, P., Cordeiro-Stone, M., Sancar, A., & Kaufmann, W. K. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02190-06 · Cited by 240 · see citing works
Ahn, J., Urist, M. J., & Prives, C. L. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.03.033 · Cited by 240 · see citing works
PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2
Yang, S., Kuo, C. S., Bisi, J., & Kim, M. K. (2002) · Nature Cell Biology · doi:10.1038/ncb869 · Cited by 238 · see citing works
The role of BRCA1 in DNA damage response
Wu, J., Lu, L.-Y., & Yu, X. (2010) · Protein & Cell · doi:10.1007/s13238-010-0010-5 · Cited by 235 · see citing works
Chk1 Kinase Negatively Regulates Mitotic Function of Cdc25A Phosphatase through 14-3-3 Binding
Chen, M.-S., Ryan, C. E., & Piwnica-Worms, H. M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.21.7488-7497.2003 · Cited by 234 · see citing works
p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2Preprint
Urist, M. J., Tanaka, T., Poyurovsky, M. V., & Prives, C. L. (2004) · Genes & Development · doi:10.1101/gad.1221004 · Cited by 234 · see citing works
Functional interrogation of DNA damage response variants with base editing screens
Cuella-Martin, R., Hayward, S. B., Fan, X., Chen, X., Huang, J., Taglialatela, A., Leuzzi, G., Zhao, J., Rabadán, R., Lü, C., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.041 · Cited by 233 · see citing works
Li, J., Williams, B. L., Haire, L. F., Goldberg, M., Wilker, E., Durocher, D., Yaffe, M. B., Jackson, S. P., & Smerdon, S. J. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00527-0 · Cited by 229 · see citing works
van Vugt, M. A. T. M., Gardino, A. K., Linding, R., Ostheimer, G. J., Reinhardt, H. C., Ong, S.-E., Tan, C. S. H., Miao, H., Keezer, S. M., Li, J., et al. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000287 · Cited by 228 · see citing works
The Role of Cdc25A in the Regulation of Cell Proliferation and Apoptosis
Shen, T., & Huang, S. (2012) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152012800617678 · Cited by 227 · see citing works
Cellular Responses to DNA Damage: One Signal, Multiple Choices
Su, T. T. (2006) · Annual Review of Genetics · doi:10.1146/annurev.genet.40.110405.090428 · Cited by 227 · see citing works
The ubiquitous role of ubiquitin in the DNA damage response
Al-Hakim, A., Escribano‐Diaz, C., Landry, M.-C., O’Donnell, L., Panier, S., Szilard, R. K., & Durocher, D. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.09.011 · Cited by 224 · see citing works
Ma, C. X., Cai, S., Li, S., Ryan, C. E., Guo, Z., Schaiff, W. T., Li, L., Hoog, J., Goiffon, R., Prat, A., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58765 · Cited by 224 · see citing works
The CHEK2 gene and inherited breast cancer susceptibility
Nevanlinna, H. A., & Bártek, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209877 · Cited by 221 · see citing works
Cell cycle control as a basis for cancer chemoprevention through dietary agents
Meeran, S. M. (2007) · Frontiers in bioscience · doi:10.2741/2834 · Cited by 220 · see citing works
Savitsky, P. A., & Finkel, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201589200 · Cited by 218 · see citing works
- Authors
- Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J., & Lukas, J.
- Affiliations
- Danish Cancer Society (DK)
- Venue
- Nature
- Published
- 2001-04
- Volume
- 410
- Issue
- 6830
- Pages
- 842-847
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1480741751
- Cited by
- 1,085
- References
- 30
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 22 · 2023: 20 · 2022: 24 · 2021: 29 · 2020: 19 · 2019: 31 · 2018: 24 · 2017: 30 · 2016: 40 · 2015: 30 · 2014: 37 · 2013: 43 · 2012: 55
- FWCI
- 29.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- radioresistant DNA synthesis, ATM, Chk2, CDC25A, CDK2, S-phase checkpoint, ionizing radiation, DNA damage response, tumour suppressor, ataxia telangiectasia, DNA replication inhibition, protein phosphorylation
- MeSH terms
- Alleles, Animals, Cell Cycle, Cell Line, DNA Replication, DNA-Binding Proteins, Humans, Phosphorylation, Protein Kinases, Radiation Tolerance, Radiation, Ionizing, Serine, Transfection, Signal Transduction, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, cdc25 Phosphatases, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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