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Leukemia, in particular, is expected to yield high therapeutic efficacy due to its high replication stress. However, the DNA damage response factors involved in the vulnerability to checkpoint inhibitors of these hematopoietic cancers remain elusive. In this study, we reveal common factors required for cellular resistance to ATR inhibition in hematopoietic cancer cells. We explored the DNA damage response pathways contributing to cellular tolerance to three types of ATR inhibitors using an isogenic DNA repair factor mutant collection derived from the chicken lymphoma cell line, DT40. We first demonstrated significant ATR inhibition activity of the recently developed Torin2 analogous compounds, SPK67 and SPK98, under stressed replication conditions. We then compared cellular sensitivity patterns of the known ATR inhibitor, VE-821, and the potential ATR inhibitors, SPK67 and SPK98, in 24 types of mutants deficient in genome maintenance systems and found that RAD17\/\u2212, FEN1\u2212\/\u2212, and POLB\u2212\/\u2212 cells exhibited hypersensitivity to all these drugs. Consistently, these mutant cells exhibited increased chromosome instability upon treatment with VE-821, SPK67, and SPK98, resulting in apoptosis. These results suggest that Rad17, Fen1, and Polymerase \u03b2 play roles in responding to DNA damage caused by these drugs. However, ATR inhibition did not result in cell-cycle arrest, Chk1 phosphorylation, or increased \u03b3H2AX levels. These results suggest that, although ATR inhibition causes DNA damage, impaired checkpoint function suppresses the appropriate activation of DNA damage signaling pathways, thereby leading to cell death. This study is the first to demonstrate the importance of Rad17, Fen1, and Polymerase \u03b2 in cellular tolerance to ATR inhibition in hematopoietic cells.<\/jats:p>","DOI":"10.3390\/biom16060851","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:50:58Z","timestamp":1781157058000},"page":"851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Common DNA Damage Response Factors Required for Cellular Resistance to Inhibitors for the Ataxia Telangiectasia and Rad3-Related Checkpoint Kinase in Hematopoietic Cells"],"prefix":"10.3390","volume":"16","author":[{"given":"Muhammad","family":"Tufail","sequence":"first","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji-shi 192-0397, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6527-6329","authenticated-orcid":false,"given":"Ryotaro","family":"Kawasumi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji-shi 192-0397, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangita Dattatray","family":"Shinde","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382055, Gujarat, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7200-7602","authenticated-orcid":false,"given":"Sivapriya","family":"Kirubakaran","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382055, Gujarat, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-979X","authenticated-orcid":false,"given":"Kouji","family":"Hirota","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji-shi 192-0397, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1016\/j.molcel.2022.05.004","article-title":"Hallmarks of DNA replication stress","volume":"82","author":"Saxena","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ncb2897","article-title":"Causes and consequences of replication stress","volume":"16","author":"Zeman","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1007\/s00018-017-2474-4","article-title":"S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion","volume":"74","author":"Giannattasio","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1038\/s41467-017-01401-x","article-title":"ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1","volume":"8","author":"Moiseeva","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13374","DOI":"10.1073\/pnas.1903418116","article-title":"An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication","volume":"116","author":"Moiseeva","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb1145","article-title":"ATR and ATM regulate the timing of DNA replication origin firing","volume":"6","author":"Shechter","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1038\/s41467-023-39332-5","article-title":"ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion","volume":"14","author":"Menolfi","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6968","DOI":"10.1158\/0008-5472.CAN-13-3369","article-title":"ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses","volume":"74","author":"Martin","year":"2014","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.radonc.2017.09.043","article-title":"ATR\/CHK1 inhibitors and cancer therapy","volume":"126","author":"Qiu","year":"2018","journal-title":"Radiother. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112792","DOI":"10.1016\/j.celrep.2023.112792","article-title":"ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms","volume":"42","author":"Leung","year":"2023","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3683","DOI":"10.1158\/0008-5472.CAN-13-0110","article-title":"ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status","volume":"73","author":"Huntoon","year":"2013","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2300635","DOI":"10.1200\/PO.23.00635","article-title":"Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses","volume":"8","author":"Konstantinopoulos","year":"2024","journal-title":"JCO Precis. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1182\/bloodadvances.2017015214","article-title":"Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase","volume":"2","author":"Fordham","year":"2018","journal-title":"Blood Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/s41467-017-00221-3","article-title":"ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways","volume":"8","author":"Le","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s41568-024-00763-x","article-title":"The present and future of the Cancer Dependency Map","volume":"25","author":"Arafeh","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D955","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of Drug Sensitivity in Cancer (GDSC): A resource for therapeutic biomarker discovery in cancer cells","volume":"41","author":"Yang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-12-380888-2.00003-0","article-title":"The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer","volume":"108","author":"Smith","year":"2010","journal-title":"Adv. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev.biochem.73.011303.073723","article-title":"Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints","volume":"73","author":"Sancar","year":"2004","journal-title":"Annu. Rev. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102921","DOI":"10.1016\/j.dnarep.2020.102921","article-title":"Mammalian DNA base excision repair: Dancing in the moonlight","volume":"93","author":"Caldecott","year":"2020","journal-title":"DNA Repair"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.dnarep.2007.02.002","article-title":"Fanconi anemia and DNA replication repair","volume":"6","author":"Patel","year":"2007","journal-title":"DNA Repair"},{"key":"ref_21","first-page":"51","article-title":"Regulation of repair pathway choice at two-ended DNA double-strand breaks","volume":"803\u2013805","author":"Shibata","year":"2017","journal-title":"Mutat. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.dnarep.2016.05.015","article-title":"Molecular mechanisms of DNA damage recognition for mammalian nucleotide excision repair","volume":"44","author":"Sugasawa","year":"2016","journal-title":"DNA Repair"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.tcb.2022.04.010","article-title":"DNA single-strand break repair and human genetic disease","volume":"32","author":"Caldecott","year":"2022","journal-title":"Trends Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102837","DOI":"10.1016\/j.dnarep.2020.102837","article-title":"Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC)","volume":"89","author":"Sun","year":"2020","journal-title":"DNA Repair"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Abe, T., Branzei, D., and Hirota, K. (2018). DNA Damage Tolerance Mechanisms Revealed from the Analysis of Immunoglobulin V Gene Diversification in Avian DT40 Cells. Genes, 9.","DOI":"10.3390\/genes9120614"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nchembio.573","article-title":"Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR","volume":"7","author":"Reaper","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105918","DOI":"10.1016\/j.esmoop.2025.105918","article-title":"A phase II, multicenter, open-label, single-arm study of berzosertib plus topotecan in patients with relapsed platinum-resistant small-cell lung cancer (DDRiver SCLC 250)","volume":"11","author":"Navarro","year":"2026","journal-title":"ESMO Open"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/17568919.2026.2620367","article-title":"Recent advances in small molecule ATR kinase inhibitors as anticancer agents","volume":"18","author":"Singh","year":"2026","journal-title":"Future Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109538","DOI":"10.1016\/j.bioorg.2026.109538","article-title":"ATR inhibitors: From targeting the DNA damage response to exploiting synthetic lethality-A paradigm shift in Cancer therapy","volume":"171","author":"Zhou","year":"2026","journal-title":"Bioorg. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5213","DOI":"10.1158\/1078-0432.CCR-21-1032","article-title":"Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study","volume":"27","author":"Yap","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1158\/1535-7163.MCT-23-0094","article-title":"Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models","volume":"23","author":"Pusch","year":"2024","journal-title":"Mol. Cancer Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/s41591-023-02399-0","article-title":"Camonsertib in DNA damage response-deficient advanced solid tumors: Phase 1 trial results","volume":"29","author":"Yap","year":"2023","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1158\/1535-7163.MCT-20-1026","article-title":"Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents","volume":"20","author":"Jo","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1158\/0008-5472.CAN-12-1702","article-title":"Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR","volume":"73","author":"Liu","year":"2013","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127517","DOI":"10.1016\/j.bmcl.2020.127517","article-title":"Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor","volume":"30","author":"Bhakuni","year":"2020","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0092-8674(91)90581-I","article-title":"Increased ratio of targeted to random integration after transfection of chicken B cell lines","volume":"67","author":"Buerstedde","year":"1991","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Okuda, M., Kawasumi, R., and Hirota, K. (2026). Generation of Human Haematopoietic Model Cell Lines Revealed Distinct Replication Stress Tolerance Between Two Oncogenic KRAS Mutations, G12V and A146T. Biomolecules, in press.","DOI":"10.3390\/biom16020204"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1289\/ehp.0900842","article-title":"A novel approach using DNA-repair-deficient chicken DT40 cell lines for screening and characterizing the genotoxicity of environmental contaminants","volume":"117","author":"Ji","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/cas.70285","article-title":"Targeting Genome Maintenance Defects of Cancers Using Chain-Terminating Nucleoside Analogs","volume":"117","author":"Kawasumi","year":"2026","journal-title":"Cancer Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ooka, M., Abe, T., Cho, K., Koike, K., Takeda, S., and Hirota, K. (2018). Chromatin remodeler ALC1 prevents replication-fork collapse by slowing fork progression. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192421"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hirota, K., Sonoda, E., Kawamoto, T., Motegi, A., Masutani, C., Hanaoka, F., Sz\u00fcts, D., Iwai, S., Sale, J.E., and Lehmann, A. (2010). Simultaneous disruption of two DNA polymerases, Pol\u03b7 and Pol\u03b6, in Avian DT40 cells unmasks the role of Pol\u03b7 in cellular response to various DNA lesions. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001151"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103773","DOI":"10.1016\/j.dnarep.2024.103773","article-title":"The flap endonuclease-1 mediated maturation of Okazaki fragments is critical for the cellular tolerance to remdesivir","volume":"144","author":"Rahman","year":"2024","journal-title":"DNA Repair"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/em.20113","article-title":"Generation of loss of heterozygosity and its dependency on p53 status in human lymphoblastoid cells","volume":"45","author":"Honma","year":"2005","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103787","DOI":"10.1016\/j.dnarep.2024.103787","article-title":"PrimPol-mediated repriming elicits gap-filling by template switching and promotes cellular tolerance to cidofovir","volume":"145","author":"Washif","year":"2025","journal-title":"DNA Repair"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/gtc.12929","article-title":"XRCC1 counteracts poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib, and a clinical alkylating agent, temozolomide, by promoting the removal of trapped PARP1 from broken DNA","volume":"27","author":"Hirota","year":"2022","journal-title":"Genes Cells"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1093\/emboj\/17.2.598","article-title":"Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death","volume":"17","author":"Sonoda","year":"1998","journal-title":"EMBO J."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Washif, M., Kawasumi, R., and Hirota, K. (2024). REV3 promotes cellular tolerance to 5-fluorodeoxyuridine by activating translesion DNA synthesis and intra-S checkpoint. PLoS Genet., 20.","DOI":"10.1371\/journal.pgen.1011341"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1021\/acs.jcim.0c01480","article-title":"Reaction Mechanism Generator v3.0: Advances in Automatic Mechanism Generation","volume":"61","author":"Liu","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1021\/c160017a018","article-title":"The Generation of a Unique Machine Description for Chemical Structures-A Technique Developed at Chemical Abstracts Service","volume":"5","author":"Morgan","year":"1965","journal-title":"J. Chem. Doc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1021\/ci9800211","article-title":"Chemical Similarity SearchingClick to copy article link","volume":"38","author":"Willett","year":"1998","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9677","DOI":"10.1074\/jbc.C300554200","article-title":"UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress","volume":"279","author":"Ward","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"42462","DOI":"10.1074\/jbc.C100466200","article-title":"ATM phosphorylates histone H2AX in response to DNA double-strand breaks","volume":"276","author":"Burma","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Huff, S.E., Winter, J.M., and Dealwis, C.G. (2022). Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present. Biomolecules, 12.","DOI":"10.3390\/biom12060815"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1016\/j.cell.2022.04.013","article-title":"mTOR substrate phosphorylation in growth control","volume":"185","author":"Battaglioni","year":"2022","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"190156","DOI":"10.1098\/rsob.190156","article-title":"A consensus set of genetic vulnerabilities to ATR inhibition","volume":"9","author":"Hustedt","year":"2019","journal-title":"Open Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.molcel.2015.07.029","article-title":"Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase","volume":"59","author":"Buisson","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1101\/gad.351084.123","article-title":"ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy","volume":"37","author":"Wang","year":"2023","journal-title":"Genes Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1111\/cas.15845","article-title":"Emerging strategies for cancer therapy by ATR inhibitors","volume":"114","author":"Yano","year":"2023","journal-title":"Cancer Sci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Bilousova, G., Marusyk, A., Porter, C.C., Cardiff, R.D., and DeGregori, J. (2005). Impaired DNA replication within progenitor cell pools promotes leukemogenesis. PLoS Biol., 3.","DOI":"10.1371\/journal.pbio.0030401"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cell.2008.01.025","article-title":"Hematopoiesis: An evolving paradigm for stem cell biology","volume":"132","author":"Orkin","year":"2008","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/cr.2008.7","article-title":"XRCC1 and DNA polymerase beta in cellular protection against cytotoxic DNA single-strand breaks","volume":"18","author":"Horton","year":"2008","journal-title":"Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1016\/j.molcel.2025.04.015","article-title":"Uracil-induced replication stress drives mutations, genome instability, anti-cancer treatment efficacy, and resistance","volume":"85","author":"Mortusewicz","year":"2025","journal-title":"Mol. Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/s41416-020-1016-2","article-title":"Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models","volume":"123","author":"Dunlop","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/1541-7786.MCR-14-0240","article-title":"A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function","volume":"13","author":"Menezes","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1158\/1535-7163.MCT-16-0378","article-title":"AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells","volume":"16","author":"Min","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1158\/0008-5472.CAN-16-3398","article-title":"ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma","volume":"77","author":"Schmitt","year":"2017","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.dnarep.2010.09.012","article-title":"The ATR barrier to replication-born DNA damage","volume":"9","year":"2010","journal-title":"DNA Repair"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1101\/gad.950302","article-title":"Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin","volume":"16","author":"Zou","year":"2002","journal-title":"Genes Dev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1158\/1535-7163.MCT-16-0239","article-title":"Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei","volume":"16","author":"Dillon","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/cddis.2012.181","article-title":"Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation","volume":"3","author":"Fokas","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/dvdy.20149","article-title":"Telomerase activity and differential expression of telomerase genes and c-myc in chicken cells in vitro","volume":"231","author":"Swanberg","year":"2004","journal-title":"Dev. Dyn."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"7002","DOI":"10.1038\/sj.onc.1203172","article-title":"Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation","volume":"18","author":"Takao","year":"1999","journal-title":"Oncogene"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"18469","DOI":"10.1074\/jbc.M411864200","article-title":"DNA polymerase lambda mediates a back-up base excision repair activity in extracts of mouse embryonic fibroblasts","volume":"280","author":"Braithwaite","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.dnarep.2007.01.011","article-title":"Interplay between DNA polymerases beta and lambda in repair of oxidation DNA damage in chicken DT40 cells","volume":"6","author":"Tano","year":"2007","journal-title":"DNA Repair"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/sj.emboj.7600534","article-title":"Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM","volume":"24","author":"Hirano","year":"2005","journal-title":"EMBO J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1158\/0008-5472.CAN-23-0628","article-title":"BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality","volume":"83","author":"Murai","year":"2023","journal-title":"Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1038\/onc.2014.276","article-title":"ATR inhibition preferentially targets homologous recombination-deficient tumor cells","volume":"34","author":"Krajewska","year":"2015","journal-title":"Oncogene"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/nar\/gkad1054","article-title":"PRIMPOL ensures robust handoff between on-the-fly and post-replicative DNA lesion bypass","volume":"52","author":"Mellor","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1091\/mbc.E20-09-0583","article-title":"SuperPlotsOfData-a web app for the transparent display and quantitative comparison of continuous data from different conditions","volume":"32","author":"Goedhart","year":"2021","journal-title":"Mol. Biol. Cell"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Shaik, A., Bhakuni, R., and Kirubakaran, S. (2018). Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR\/mTOR Kinase Inhibitors. 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