The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair
Abstract
The essential checkpoint kinase Chk1 is required for cell-cycle delays after DNA damage or blocked DNA replication. However, it is unclear whether Chk1 is involved in the repair of damaged DNA. Here we establish that Chk1 is a key regulator of genome maintenance by the homologous recombination repair (HRR) system. Abrogation of Chk1 function with small interfering RNA or chemical antagonists inhibits HRR, leading to persistent unrepaired DNA double-strand breaks (DSBs) and cell death after replication inhibition with hydroxyurea or DNA-damage caused by camptothecin. After hydroxyurea treatment, the essential recombination repair protein RAD51 is recruited to DNA repair foci performing a vital role in correct HRR. We demonstrate that Chk1 interacts with RAD51, and that RAD51 is phosphorylated on Thr 309 in a Chk1-dependent manner. Consistent with a functional interplay between Chk1 and RAD51, Chk1-depleted cells failed to form RAD51 nuclear foci after exposure to hydroxyurea, and cells expressing a phosphorylation-deficient mutant RAD51(T309A) were hypersensitive to hydroxyurea. These results highlight a crucial role for the Chk1 signalling pathway in protecting cells against lethal DNA lesions through regulation of HRR.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [27]
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 [27]
Active Chk1 phosphorylates Rad51, a protein involved in homologous recombination repair of double-strand breaks.
“activated Chk1 phosphorylates its own substrates such as protein Rad51, which is involved in the DSB repair by HR [193–195]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [195]
Cites
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
Liu, Q., Guntuku, S., Cui, X.-S., Matsuoka, S., Cortez, D., Tamai, K., Luo, G., Carattini-Rivera, S., DeMayo, F., Bradley, A., et al. (2000) · Genes & Development · doi:10.1101/gad.14.12.1448 · Cited by 1,625 · 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
Sensing and repairing DNA double-strand breaks
Jackson, S. P. (2002) · Carcinogenesis · doi:10.1093/carcin/23.5.687 · Cited by 1,126 · see citing works
ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1
Zhao, H., & Piwnica-Worms, H. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.13.4129-4139.2001 · Cited by 1,091 · see citing works
(1999) · PubMed · Cited by 1,030 · see citing works
<i>ATR</i> disruption leads to chromosomal fragmentation and early embryonic lethality
Brown, E. J., & Baltimore, D. (2000) · Genes & Development · doi:10.1101/gad.14.4.397 · Cited by 951 · see citing works
Molecular views of recombination proteins and their control
West, S. C. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1127 · Cited by 947 · see citing works
Rad51‐deficient vertebrate cells accumulate chromosomal breaks prior to cell death
Sonoda, E., Sasaki, M., Buerstedde, J., Bezzubova, O., Shinohara, A., Ogawa, H., Takata, M., Yamaguchi-Iwai, Y., & Takeda, S. (1998) · EMBO Journal · doi:10.1093/emboj/17.2.598 · Cited by 860 · see citing works
Targeted disruption of the Rad51 gene leads to lethality in embryonic mice.
Tsuzuki, T., Fujii, Y., Sakumi, K., Tominaga, Y., Nakao, K., Sekiguchi, M., Matsushiro, A., Yoshimura, Y., & MoritaT (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6236 · Cited by 792 · see citing works
The DNA replication checkpoint response stabilizes stalled replication forks
Lopes, M., Cotta‐Ramusino, C., Pellicioli, A., Liberi, G., Plevani, P., Muzi-Falconi, M., Newlon, C. S., & Foiani, M. (2001) · Nature · doi:10.1038/35087613 · Cited by 749 · see citing works
Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint
Tercero, J. A., & Diffley, J. F. X. (2001) · Nature · doi:10.1038/35087607 · Cited by 667 · see citing works
S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex
Katou, Y., Kanoh, Y., Bando, M., Noguchi, H., Tanaka, H., Ashikari, T., Sugimoto, K., & Shirahige, K. (2003) · Nature · doi:10.1038/nature01900 · Cited by 649 · see citing works
Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systemsPreprint
Liu, M., Pereira, F. A., Price, S. D., Chu, M.-J., Shope, C. D., Himes, D., Eatock, R. A., Brownell, W. E., Lysakowski, A., & Tsai, M. (2000) · Genes & Development · doi:10.1101/gad.840500 · Cited by 625 · see citing works
Johnson, R. D., & Jasin, M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.13.3398 · Cited by 590 · 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-citationATR Regulates Fragile Site Stability
Casper, A. M., Nghiem, P., Arlt, M. F., & Glover, T. W. (2002) · Cell · doi:10.1016/s0092-8674(02)01113-3 · Cited by 559 · see citing works
Haaf, T., Golub, E. I., Reddy, G., Radding, C. M., & Ward, D. C. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.6.2298 · Cited by 552 · see citing works
Cliby, W. A., Roberts, C. J., Cimprich, K. A., Stringer, C. M., Lamb, J. R., Schreiber, S. L., & Friend, S. H. (1998) · The EMBO Journal · doi:10.1093/emboj/17.1.159 · Cited by 534 · see citing works
Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance
Brown, E. J., & Baltimore, D. (2003) · Genes & Development · doi:10.1101/gad.1067403 · Cited by 511 · see citing works
Aberrant cell cycle checkpoint function and early embryonic death in Chk1−/− micePreprint
Takai, H., Tominaga, K., Motoyama, N., Minamishima, Y. A., Nagahama, H., Tsukiyama, T., Ikeda, K., Nakayama, K., Nakanishi, M., & Nakayama, K. (2000) · Genes & Development · doi:10.1101/gad.14.12.1439 · Cited by 478 · see citing works
Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice
de Klein, A., Muijtjens, M., van Os, R. P., Verhoeven, Y., Smit, B., Carr, A. M., Lehmann, A. R., & Hoeijmakers, J. H. J. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00447-4 · Cited by 437 · see citing works
Luo, G., Yao, M. S., Bender, C. F., Mills, M., Bladl, A. R., Bradley, A., & Petrini, J. H. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7376 · Cited by 408 · see citing works
Arnaudeau, C., Lundin, C., & Helleday, T. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.4564 · Cited by 387 · see citing works
Self-citationCharacterization of homologous recombination induced by replication inhibition in mammalian cells
Saintigny, Y., Delacôte, F., Varès, G., Petitot, F., Lambert, S., Averbeck, D., & López, B. S. (2001) · The EMBO Journal · doi:10.1093/emboj/20.14.3861 · Cited by 334 · 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
(2000) · PubMed · Cited by 314 · see citing works
Saleh-Gohari, N. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh703 · Cited by 270 · see citing works
Tebbs, R. S., Zhao, Y., Tucker, J. D., Scheerer, J. B., Siciliano, M., Hwang, M. S., Liu, N., Legerski, R. J., & Thompson, L. H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.14.6354 · Cited by 257 · see citing works
Mediator function of the human Rad51B–Rad51C complex in Rad51/RPA-catalyzed DNA strand exchangePreprint
Sigurðsson, S., Komen, S. V., Bussen, W., Schild, D., Albala, J. S., & Sung, P. (2001) · Genes & Development · doi:10.1101/gad.935501 · Cited by 257 · see citing works
Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice
Deans, B., Griffin, C. S., Maconochie, M. K., & Thacker, J. (2000) · The EMBO Journal · doi:10.1093/emboj/19.24.6675 · Cited by 250 · see citing works
Lundin, C., Erixon, K., Arnaudeau, C., Schultz, N., Jenssen, D., Meuth, M., & Helleday, T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.16.5869-5878.2002 · Cited by 234 · see citing works
Self-citationDefects in homologous recombination repair in mismatch-repair-deficient tumour cell lines
Mohindra, A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.18.2189 · Cited by 76 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The DNA Damage Response: Making It Safe to Play with Knives
Ciccia, A., & Elledge, S. J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.019 · Cited by 4,368 · 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
Self-citationDNA Damage Sensing by the ATM and ATR Kinases
Marechal, A., & Zou, L. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012716 · Cited by 1,514 · see citing works
McCabe, N., Turner, N. C., Lord, C. J., Kluzek, K., Białkowska, A., Swift, S., Giavara, S., O’Connor, M. J., Tutt, A. N. J., Zdzienicka, M. Z., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0140 · Cited by 1,311 · see citing works
The ATM–Chk2 and ATR–Chk1 Pathways in DNA Damage Signaling and Cancer
Smith, J., Tho, L. M., Xu, N., & Gillespie, D. A. (2010) · Advances in cancer research · doi:10.1016/b978-0-12-380888-2.00003-0 · Cited by 1,279 · see citing works
Regulation of DNA repair throughout the cell cycle
Branzei, D., & Foiani, M. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2351 · Cited by 1,228 · see citing works
Regulation of Homologous Recombination in Eukaryotes
Heyer, W.-D., Ehmsen, K. T., & Liu, J. (2010) · Annual Review of Genetics · doi:10.1146/annurev-genet-051710-150955 · Cited by 1,066 · see citing works
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C. M., Lukas, J., & Jackson, S. P. (2006) · Nature Cell Biology · doi:10.1038/ncb1337 · Cited by 1,064 · see citing works
Petermann, E., Orta, M. L., Issaeva, N., Schultz, N., & Helleday, T. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.021 · Cited by 815 · see citing works
Self-citationOpportunities and challenges of radiotherapy for treating cancer
Schaue, D., & McBride, W. H. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.120 · Cited by 784 · see citing works
Homologous recombination and its regulation
Krejčí, L., Altmannová, V., Spirek, M., & Zhao, X. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks270 · Cited by 642 · 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
ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1
Zhang, P., Wei, Y., Wang, L., Debeb, B. G., Yuan, Y., Zhang, J., Yuan, J., Wang, M., Chen, D., Sun, Y., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3013 · Cited by 454 · see citing works
New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network
Dai, Y., & Grant, S. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1029 · Cited by 438 · see citing works
Targeting replication stress in cancer therapy
da Costa, A. A. B. A., Chowdhury, D., Shapiro, G. I., D’Andrea, A. D., & Konstantinopoulos, P. A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00558-5 · Cited by 380 · see citing works
ATR/CHK1 inhibitors and cancer therapy
Qiu, Z., Oleinick, N. L., & Zhang, J. (2017) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2017.09.043 · Cited by 378 · see citing works
RTEL1 Maintains Genomic Stability by Suppressing Homologous Recombination
Barber, L. J., Youds, J. L., Ward, J. D., McIlwraith, M. J., O'Neil, N. J., Petalcorin, M. I. R., Martin, J. S., Collis, S. J., Cantor, S. B., Auclair, M., et al. (2008) · Cell · doi:10.1016/j.cell.2008.08.016 · Cited by 369 · see citing works
Thompson, L. H. (2012) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2012.06.002 · Cited by 357 · see citing works
DNA damage checkpoint kinases in cancer
Smith, H. L., Southgate, H. E. D., Tweddle, D. A., & Curtin, N. J. (2020) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2020.3 · Cited by 323 · see citing works
Checkpoint kinase 1 in DNA damage response and cell cycle regulation
Patil, M., Pabla, N., & Dong, Z. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1307-3 · Cited by 317 · see citing works
Sørensen, C. S., & Syljuåsen, R. G. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr697 · Cited by 316 · see citing works
Self-citationRAD18 transmits DNA damage signalling to elicit homologous recombination repair
Huang, J., Huen, M. S. Y., Kim, H., Leung, C. C. Y., Glover, J. N. M., Yu, X., & Chen, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1865 · Cited by 303 · see citing works
Beck, H., Nähse, V., Larsen, M. S. Y., O’Hanlon, K. A., Patzke, S., Holmberg, C., Mejlvang, J., Groth, A., Nielsen, O., Syljuåsen, R. G., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00412-12 · Cited by 303 · see citing works
Self-citationExploiting 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
Self-citationMorgan, M. A., Parsels, L. A., Zhao, L., Parsels, J. D., Davis, M. A., Hassan, M. C., Arumugarajah, S., Hylander-Gans, L., Morosini, D., Simeone, D. M., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3573 · Cited by 299 · see citing works
Mladenov, E., Magin, S., Soni, A., & Iliakis, G. E. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00113 · Cited by 292 · see citing works
Repair of Topoisomerase I‐Mediated DNA Damage
Pommier, Y. G., Barceló, J. M., Rao, V. A., Sordet, O., Jobson, A. G., Thibaut, L., Miao, Z., Seiler, J. A., Zhang, H., Marchand, C., et al. (2006) · Progress in nucleic acid research and molecular biology · doi:10.1016/s0079-6603(06)81005-6 · Cited by 288 · see citing works
Homologous recombination in cancer development, treatment and development of drug resistance
Helleday, T. (2010) · Carcinogenesis · doi:10.1093/carcin/bgq064 · Cited by 288 · see citing works
Self-citationWee1 kinase as a target for cancer therapy
Do, K. T., Doroshow, J. H., & Kummar, S. (2013) · Cell Cycle · doi:10.4161/cc.26062 · Cited by 279 · see citing works
DNA Damage Response Genes and the Development of Cancer Metastasis
Broustas, C. G., & Lieberman, H. B. (2014) · Radiation Research · doi:10.1667/rr13515.1 · Cited by 276 · see citing works
GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer
Lin, J., Song, T., Li, C., & Mao, W. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118659 · Cited by 275 · see citing works
DNA Damage Response: Three Levels of DNA Repair Regulation
Sirbu, B. M., & Cortez, D. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012724 · Cited by 272 · 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
DNA damage kinase signaling: checkpoint and repair at 30 years
Lanz, M. C., Dibitetto, D., & Smolka, M. B. (2019) · The EMBO Journal · doi:10.15252/embj.2019101801 · Cited by 259 · 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
Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
Participation of DNA repair in the response to 5-fluorouracil
Wyatt, M. D., & Wilson, D. M. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8557-5 · Cited by 245 · see citing works
Stracker, T. H., Usui, T., & Petrini, J. H. J. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.04.012 · Cited by 245 · see citing works
Targeting the ATR-CHK1 Axis in Cancer Therapy
Rundle, S., Bradbury, A., Drew, Y., & Curtin, N. J. (2017) · Cancers · doi:10.3390/cancers9050041 · Cited by 235 · see citing works
Biomarker-Guided Development of DNA Repair Inhibitors
Cleary, J. M., Aguirre, A. J., Shapiro, G. I., & D’Andrea, A. D. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.035 · Cited by 231 · see citing works
Replication Catastrophe: When a Checkpoint Fails because of Exhaustion
Toledo, L. I., Neelsen, K. J., & Lukas, J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.001 · Cited by 228 · see citing works
The histone methyltransferase SET8 is required for S-phase progression
Jørgensen, S., Elvers, I., Trelle, M. B., Menzel, T., Eskildsen, M., Jensen, O. N., Helleday, T., Helin, K., & Sørensen, C. S. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200706150 · Cited by 225 · see citing works
Self-citationTrenz, K., Smith, E., Smith, S. J., & Costanzo, V. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601045 · Cited by 219 · see citing works
Proteasome Function Is Required for DNA Damage Response and Fanconi Anemia Pathway Activation
Jacquemont, C. F., & Taniguchi, T. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1015 · Cited by 212 · see citing works
DNA repair defects in cancer and therapeutic opportunitiesPreprint
Hopkins, J. L., Lan, L., & Zou, L. (2022) · Genes & Development · doi:10.1101/gad.349431.122 · Cited by 204 · see citing works
Peasland, A., Wang, L.-Z., Rowling, E. J., Kyle, S., Chen, T., Hopkins, A. P., Cliby, W. A., Sarkaria, J. N., Beale, G., Edmondson, R. J., et al. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.243 · Cited by 197 · see citing works
Cuneo, K. C., Morgan, M. A., Sahai, V., Schipper, M. J., Parsels, L. A., Parsels, J. D., Devasia, T. P., Al-Hawaray, M., Cho, C. S., Nathan, H., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.19.00730 · Cited by 193 · see citing works
Nojima, K., Hochegger, H., Saberi, A., Fukushima, T., Kikuchi, K., Yoshimura, M., Orelli, B. J., Bishop, D. K., Hirano, S., Ohzeki, M., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1214 · Cited by 185 · see citing works
Chk1 and p21 Cooperate to Prevent Apoptosis during DNA Replication Fork Stress
Rodrı́guez, R., & Meuth, M. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-07-0594 · Cited by 183 · see citing works
Coupling of Homologous Recombination and the Checkpoint by ATR
Buisson, R., Joshi, N., Rodrigue, A., Ho, C. K., Kreuzer, J., Foo, T. K., Hardy, É. J.-L., Dellaire, G., Haas, W., Xia, B., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2016.12.007 · Cited by 181 · see citing works
Bahassi, E. M., Ovesen, J. L., Riesenberg, A. L., Bernstein, W. Z., Hasty, P., & Stambrook, P. J. (2008) · Oncogene · doi:10.1038/onc.2008.17 · Cited by 180 · see citing works
Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?
Bradbury, A., Hall, S., Curtin, N. J., & Drew, Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107450 · Cited by 176 · see citing works
Ammazzalorso, F., Pirzio, L. M., Bignami, M., Franchitto, A., & Pichierri, P. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.205 · Cited by 171 · see citing works
DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy
Carrassa, L., & Damia, G. L. M. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.08.013 · Cited by 170 · see citing works
Al-Minawi, A. Z., Saleh-Gohari, N., & Helleday, T. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm888 · Cited by 169 · see citing works
Self-citationRegulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase
Beck, H., Nähse, V., Larsen, M. S. Y., Groth, P., Clancy, T., Lees, M. J., Jørgensen, M., Helleday, T., Syljuåsen, R. G., & Sørensen, C. S. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200905059 · Cited by 169 · see citing works
Self-citationCHEK again: Revisiting the development of CHK1 inhibitors for cancer therapy
McNeely, S., Beckmann, R. P., & Bence, A. K. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.10.005 · Cited by 167 · see citing works
Defining and Modulating ‘BRCAness’
Byrum, A. K., Vindigni, A., & Mosammaparast, N. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.06.005 · Cited by 164 · see citing works
Petermann, E., & Caldecott, K. W. (2006) · Cell Cycle · doi:10.4161/cc.5.19.3256 · Cited by 163 · see citing works
Targeting the DNA Damage Response in Cancer
Ljungman, M. E. (2009) · Chemical Reviews · doi:10.1021/cr900047g · Cited by 163 · see citing works
Mechanisms of replication fork protection: a safeguard for genome stability
Errico, A., & Costanzo, V. (2012) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2012.655374 · Cited by 159 · see citing works
Loss of autophagy causes a synthetic lethal deficiency in DNA repair
Liu, E. Y., Xu, N., O’Prey, J., Lao, L., Joshi, S., Long, J. S., O’Prey, M., Croft, D. R., Beaumatin, F., Baudot, A. D., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409563112 · Cited by 159 · see citing works
Bártková, J., Tommiska, J., Oplustilova, L., Aaltonen, K., Tamminen, A., Heikkinen, T., Mistrík, M., Aittomäki, K., BLOMQVIST, C. P., Heikkilä, P., et al. (2008) · Molecular Oncology · doi:10.1016/j.molonc.2008.09.007 · Cited by 156 · see citing works
Ayllón, V., & O’Connor, R. (2006) · Oncogene · doi:10.1038/sj.onc.1210142 · Cited by 149 · see citing works
Reality CHEK: Understanding the biology and clinical potential of CHK1
Neizer‐Ashun, F., & Bhattacharya, R. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.09.016 · Cited by 149 · see citing works
Parsels, L. A., Morgan, M. A., Tanska, D. M., Parsels, J. D., Palmer, B. D., Booth, R. J., Denny, W. A., Canman, C. E., Kraker, A. J., Lawrence, T. S., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0662 · Cited by 148 · see citing works
Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
Manic, G., Obrist, F., Sistigu, A., & Vitale, I. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1012976 · Cited by 147 · see citing works
Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities
Sanjiv, K., Hagenkort, A., Calderón‐Montaño, J. M., Koolmeister, T., Reaper, P. M., Mortusewicz, O., Jacques, S. A., Kuiper, R., Schultz, N., Scobie, M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.12.032 · Cited by 147 · see citing works
Self-citationTargeting Checkpoint Kinase 1 in Cancer Therapeutics
Tse, A. N., Carvajal, R. D., & Schwartz, G. K. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2793 · Cited by 147 · see citing works
Chk1-Mediated Phosphorylation of FANCE Is Required for the Fanconi Anemia/BRCA Pathway
Wang, X., Kennedy, R. D., Ray, K., Stuckert, P., Ellenberger, T., & D’Andrea, A. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02357-06 · Cited by 147 · see citing works
Sidorova, J. M., Li, N., Folch, A., & Monnat, R. J. (2008) · Cell Cycle · doi:10.4161/cc.7.6.5566 · Cited by 146 · see citing works
Tse, A. N., Rendahl, K. G., Sheikh, T. N., Cheema, H., Aardalen, K., Embry, M. G., Ma, S., Moler, E. J., Ni, Z., de Menezes, D. E. L., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1424 · Cited by 145 · see citing works
Enhanced H2AX Phosphorylation, DNA Replication Fork Arrest, and Cell Death in the Absence of Chk1
Gagou, M. E., Zuazua‐Villar, P., & Meuth, M. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-07-0618 · Cited by 144 · see citing works
Parmar, K., Kochupurakkal, B. S., Lazaro, J., Wang, Z. C., Palakurthi, S. S., Kirschmeier, P. T., Yang, C., Sambel, L. A., Färkkilä, A., Reznichenko, E., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0448 · Cited by 143 · see citing works
The ATR barrier to replication-born DNA damage
Lopez-Contreras, A. J., & Fernández-Capetillo, Ó. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.09.012 · Cited by 138 · see citing works
Wagner, J. M., & Karnitz, L. M. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.055178 · Cited by 135 · see citing works
Targeting DNA repair pathway in cancer: Mechanisms and clinical application
Wang, M., Chen, S., & Ao, D. (2021) · MedComm · doi:10.1002/mco2.103 · Cited by 134 · see citing works
The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment
Li, S., Wang, L., Wang, Y., Zhang, C., Hong, Z., & Han, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01360-x · Cited by 133 · see citing works
Mitchell, J. B., Choudhuri, R., Fabre, K. M., Sowers, A. L., Citrin, D. E., Zabludoff, S., & Cook, J. A. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3277 · Cited by 131 · see citing works
ATR and H2AX cooperate in maintaining genome stability under replication stress
Chanoux, R. A., Yin, B., Urtishak, K. A., Asare, A., Bassing, C. H., & Brown, E. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806739200 · Cited by 130 · see citing works
RFWD3-Dependent Ubiquitination of RPA Regulates Repair at Stalled Replication Forks
Elia, A. E. H., Wang, D. C., Willis, N. A., Boardman, A. P., Hajdú, I., Adeyemi, R. O., Lowry, E. L., Gygi, S. P., Scully, R., & Elledge, S. J. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.011 · Cited by 129 · see citing works
SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation
Jørgensen, S., Eskildsen, M., Fugger, K., Hansen, L., Larsen, M. S. Y., Kousholt, A. N., Syljuåsen, R. G., Trelle, M. B., Jensen, O. N., Helin, K., et al. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201009076 · Cited by 128 · see citing works
Self-citationReplication fork dynamics and the DNA damage response
Jones, R. M., & Petermann, E. (2012) · Biochemical Journal · doi:10.1042/bj20112100 · Cited by 127 · see citing works
Deans, A. J., Khanna, K. K., McNees, C. J., Mercurio, C., Heierhorst, J., & McArthur, G. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3945 · Cited by 125 · see citing works
Thompson, R. H., & Eastman, A. R. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12139 · Cited by 122 · see citing works
Jekimovs, C., Bolderson, E., Suraweera, A., Adams, M. N., O'Byrne, K. J., & Richard, D. J. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00086 · Cited by 118 · see citing works
Alver, R. C., Chadha, G. S., Gillespie, P. J., & Blow, J. J. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.042 · Cited by 116 · see citing works
DNA damage control: regulation and functions of checkpoint kinase 1
Smits, V. A. J., & Gillespie, D. A. (2015) · FEBS Journal · doi:10.1111/febs.13387 · Cited by 115 · see citing works
Paulsen, B. S., Mandal, P. K., Frock, R. L., Boyraz, B., Yadav, R., Upadhyayula, S., Gutierrez‐Martinez, P., Ebina, W., Fasth, A. L., Kirchhausen, T. L., et al. (2017) · Nature Biomedical Engineering · doi:10.1038/s41551-017-0145-2 · Cited by 114 · see citing works
Luo, K., Li, L., Li, Y., Wu, C., Yin, Y., Chen, Y., Deng, M., Nowsheen, S., Yuan, J., & Lou, Z. (2016) · Genes & Development · doi:10.1101/gad.289439.116 · Cited by 114 · see citing works
HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability
Collis, S. J., Barber, L. J., Clark, A. J., Martin, J. S., Ward, J. D., & Boulton, S. J. (2007) · Nature Cell Biology · doi:10.1038/ncb1555 · Cited by 112 · see citing works
Nakamura, K. M., Sakai, W., Kawamoto, T., Bree, R. T., Lowndes, N. F., Takeda, S., & Taniguchi, Y. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.03.008 · Cited by 111 · see citing works
Targeting the Checkpoint to Kill Cancer Cells
Benada, J., & Macůrek, L. (2015) · Biomolecules · doi:10.3390/biom5031912 · Cited by 110 · see citing works
Overexpression of RAD51 occurs in aggressive prostatic cancer
Mitra, A., Jameson, C., Barbáchano, Y., Sánchez, L., Kote‐Jarai, Z., Peock, S., Sodha, N., Bancroft, E. K., Fletcher, A., Cooper, C., et al. (2009) · Histopathology · doi:10.1111/j.1365-2559.2009.03448.x · Cited by 108 · see citing works
Sensitization of Pancreatic Cancer to Chemoradiation by the Chk1 Inhibitor MK8776
Engelke, C. G., Parsels, L. A., Qian, Y., Zhang, Q., Karnak, D. M., Robertson, J. R., Tanska, D. M., Wei, D., Davis, M. A., Parsels, J. D., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3748 · Cited by 106 · see citing works
Chk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair
Chou, W., Wang, H., Wong, F., Ding, S., Wu, P., Shieh, S., & Shen, C. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.229 · Cited by 104 · see citing works
Alabert, C., Bianco, J. N., & Pasero, P. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.75 · Cited by 104 · see citing works
6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance
Issaeva, N., Thomas, H. D., Djurenovic, T., Jaspers, J. E., Stoimenov, I., Kyle, S., Pedley, N., Gottipati, P., Zur, R., Sleeth, K. M., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3416 · Cited by 104 · see citing works
Self-citationTriple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs
Wu, Q., Siddharth, S., & Sharma, D. (2021) · Cancers · doi:10.3390/cancers13153697 · Cited by 102 · see citing works
Dai, Y., Chen, S., Pei, X., Almenara, J. A., Kramer, L. B., Venditti, C. A., Dent, P., & Grant, S. (2008) · Blood · doi:10.1182/blood-2008-05-159392 · Cited by 101 · see citing works
- Authors
- Sørensen, C. S., Hansen, L. T., Dziegielewski, J., Syljuåsen, R. G., Lundin, C., Bartek, J., & Helleday, T.
- Affiliations
- Danish Cancer Society (DK)
- University of Copenhagen (DK)
- University of Sheffield (GB)
- Stockholm University (SE)
- Corresponding author
- Helleday, Thomas
- Venue
- Nature Cell Biology
- Published
- 2005-01-23
- Volume
- 7
- Issue
- 2
- Pages
- 195-201
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2149795092
- Cited by
- 666
- References
- 33
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 18 · 2023: 38 · 2022: 26 · 2021: 38 · 2020: 41 · 2019: 23 · 2018: 31 · 2017: 31 · 2016: 37 · 2015: 44 · 2014: 37 · 2013: 35 · 2012: 48
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Chk1, homologous recombination repair, RAD51, DNA double-strand break repair, DNA damage response, cell cycle checkpoints, hydroxyurea, camptothecin, genome maintenance, replication inhibition
- MeSH terms
- Checkpoint Kinase 1, Animals, Camptothecin, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Cricetinae, Humans, Hydroxyurea, Protein Kinases, Recombination, Genetic, Signal Transduction, Rad51 Recombinase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
