Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine

Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquit...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Nucleic acids research Jg. 50; H. 13; S. 7420 - 7435
Hauptverfasser:	Spanjaard, Aldo, Shah, Ronak, de Groot, Daniël, Buoninfante, Olimpia Alessandra, Morris, Ben, Lieftink, Cor, Pritchard, Colin, Zürcher, Lisa M, Ormel, Shirley, Catsman, Joyce J I, de Korte-Grimmerink, Renske, Siteur, Bjørn, Proost, Natalie, Boadum, Terry, van de Ven, Marieke, Song, Ji-Ying, Kreft, Maaike, van den Berk, Paul C M, Beijersbergen, Roderick L, Jacobs, Heinz
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England Oxford University Press 22.07.2022
Schlagworte:	Animals Cisplatin - therapeutic use DNA Damage DNA Repair DNA Replication DNA-Directed DNA Polymerase - metabolism Genome Integrity, Repair and Humans Mice Neoplasms - drug therapy Neoplasms - genetics Precision Medicine Proliferating Cell Nuclear Antigen - metabolism Ubiquitination
ISSN:	0305-1048, 1362-4962, 1362-4962
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Abstract	Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.
AbstractList	Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine. Graphical AbstractHuman and murine cell lines and mice rely on PCNA-ubiquitination, though not REV1, to tolerate cisplatin-induced DNA interstrand crosslinks. TLS polymerase Kappa deficiency sensitises tumors to cisplatin in vitro and in vivo. Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine. Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.
Author	Pritchard, Colin Shah, Ronak Morris, Ben Buoninfante, Olimpia Alessandra Proost, Natalie Boadum, Terry Zürcher, Lisa M van den Berk, Paul C M van de Ven, Marieke Kreft, Maaike Jacobs, Heinz Siteur, Bjørn Song, Ji-Ying de Groot, Daniël Spanjaard, Aldo Ormel, Shirley Catsman, Joyce J I de Korte-Grimmerink, Renske Beijersbergen, Roderick L Lieftink, Cor
Author_xml	– sequence: 1 givenname: Aldo surname: Spanjaard fullname: Spanjaard, Aldo – sequence: 2 givenname: Ronak surname: Shah fullname: Shah, Ronak – sequence: 3 givenname: Daniël surname: de Groot fullname: de Groot, Daniël – sequence: 4 givenname: Olimpia Alessandra surname: Buoninfante fullname: Buoninfante, Olimpia Alessandra – sequence: 5 givenname: Ben surname: Morris fullname: Morris, Ben – sequence: 6 givenname: Cor surname: Lieftink fullname: Lieftink, Cor – sequence: 7 givenname: Colin surname: Pritchard fullname: Pritchard, Colin – sequence: 8 givenname: Lisa M surname: Zürcher fullname: Zürcher, Lisa M – sequence: 9 givenname: Shirley surname: Ormel fullname: Ormel, Shirley – sequence: 10 givenname: Joyce J I surname: Catsman fullname: Catsman, Joyce J I – sequence: 11 givenname: Renske surname: de Korte-Grimmerink fullname: de Korte-Grimmerink, Renske – sequence: 12 givenname: Bjørn surname: Siteur fullname: Siteur, Bjørn – sequence: 13 givenname: Natalie surname: Proost fullname: Proost, Natalie – sequence: 14 givenname: Terry surname: Boadum fullname: Boadum, Terry – sequence: 15 givenname: Marieke surname: van de Ven fullname: van de Ven, Marieke – sequence: 16 givenname: Ji-Ying surname: Song fullname: Song, Ji-Ying – sequence: 17 givenname: Maaike surname: Kreft fullname: Kreft, Maaike – sequence: 18 givenname: Paul C M surname: van den Berk fullname: van den Berk, Paul C M – sequence: 19 givenname: Roderick L surname: Beijersbergen fullname: Beijersbergen, Roderick L – sequence: 20 givenname: Heinz orcidid: 0000-0001-6227-9850 surname: Jacobs fullname: Jacobs, Heinz
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/35819193$$D View this record in MEDLINE/PubMed
BookMark	eNptkU1vEzEQhi1URNPCiTvyEQkttdfr7PqCVLV8SRVc4GyNvbOJwWsH20mVP8FvxlFSBIjTHPzO84z8XpCzEAMS8pyz15wpcRUgXa2-g5WdfEQWXCzbplPL9owsmGCy4awbzslFzt8Y4x2X3RNyLuTAFVdiQX7eup3LLgYaJ-rBxETvXVm7QMsa6e2nazrCDCukJXpMECzSvM8FZ5pwh-Azrdc0uHG5QHGWQhip9S44C97vKdhS2WB8BUBaYcl0qopNQnu02gMy0RlHZ13Ap-TxVKH47DQvydd3b7_cfGjuPr__eHN911jBeWnGvjfcSBxlD6aVSk3SyK6fJKCxRg5TN4AyrRo7ib2YhOlkL4D1PVMK5TiJS_LmyN1sTXVbDCWB15vkZkh7HcHpv1-CW-tV3GklmBCKVcDLEyDFH1vMRc8uW_QeAsZt1u1yGORS9e1Qoy_-dP2WPJRQA_wYsCnmnHDS1h1-Mx7UzmvO9KFoXYvWp6Lrzqt_dh6w_0v_AvjUsEM
CitedBy_id	crossref_primary_10_1186_s13059_024_03451_z crossref_primary_10_1038_s41594_024_01395_3 crossref_primary_10_1186_s12929_024_01044_3 crossref_primary_10_1093_pnasnexus_pgae242 crossref_primary_10_1016_j_molcel_2023_07_008 crossref_primary_10_1186_s12894_024_01410_1 crossref_primary_10_1038_s41389_024_00525_2 crossref_primary_10_1073_pnas_2216055120
Cites_doi	10.1016/j.molcel.2010.02.009 10.1016/j.cell.2008.08.030 10.1038/nature21671 10.1016/j.urolonc.2011.09.010 10.1158/0008-5472.CAN-03-3489 10.1016/j.celrep.2012.09.029 10.1038/nature09104 10.1007/s12035-017-0507-5 10.1093/nar/25.10.1913 10.1158/0008-5472.CAN-04-1328 10.1093/nar/gku1301 10.1016/j.dnarep.2011.08.005 10.1038/nprot.2013.143 10.1038/nature13619 10.1038/s41467-020-16096-w 10.1038/s41591-019-0432-4 10.1016/j.molcel.2006.03.022 10.1038/nm.4409 10.1016/j.jmb.2018.04.023 10.1186/s41021-016-0067-3 10.1084/jem.20052227 10.1126/sciadv.aaz7808 10.1038/nrm.2016.48 10.1038/nrm3562 10.1073/pnas.1011412107 10.1016/j.molcel.2012.05.001 10.1038/s41586-019-1607-3 10.1073/pnas.1011409107 10.1073/pnas.1706508114 10.1530/ERC-18-0289 10.1016/0076-6879(93)25052-4 10.1128/MCB.00993-09 10.1073/pnas.1605828113 10.1038/nature00991 10.1093/emboj/cdg626 10.1083/jcb.201702006 10.1093/nar/gki279 10.1084/jem.20070902 10.1038/nature11863 10.1038/nature14131 10.1016/j.cell.2019.05.028 10.1002/j.1460-2075.1991.tb07953.x 10.18632/oncotarget.24777 10.1038/nrc3088 10.1073/pnas.2016064117 10.1038/srep19552 10.1016/j.molcel.2020.11.029 10.1074/jbc.M117.792192 10.1371/journal.pone.0120334 10.1038/s41588-019-0471-2 10.1158/0008-5472.CAN-09-1947 10.1038/nprot.2006.5 10.1002/eji.201243191 10.1182/blood-2017-01-764274 10.1016/j.tig.2018.12.007 10.1016/j.molcel.2008.03.024 10.1074/jbc.C300023200 10.1038/s41586-019-1450-6
ContentType	Journal Article
Copyright	The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. 2022
Copyright_xml	– notice: The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. – notice: The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. 2022
DBID	AAYXX CITATION CGR CUY CVF ECM EIF NPM 7X8 5PM
DOI	10.1093/nar/gkac545
DatabaseName	CrossRef Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic PubMed Central (Full Participant titles)
DatabaseTitle	CrossRef MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic
DatabaseTitleList	CrossRef MEDLINE - Academic MEDLINE
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database
DeliveryMethod	fulltext_linktorsrc
Discipline	Anatomy & Physiology Chemistry
EISSN	1362-4962
EndPage	7435
ExternalDocumentID	PMC9303390 35819193 10_1093_nar_gkac545
Genre	Research Support, Non-U.S. Gov't Journal Article
GrantInformation_xml	– fundername: ; – fundername: ; grantid: NKI-2017-10032; NKI2017-10796
GroupedDBID	--- -DZ -~X .I3 0R~ 123 18M 1TH 29N 2WC 4.4 482 53G 5VS 5WA 70E 85S A8Z AAFWJ AAHBH AAMVS AAOGV AAPXW AAVAP AAYXX ABEJV ABGNP ABPTD ABQLI ABXVV ACGFO ACGFS ACIWK ACNCT ACPRK ACUTJ ADBBV ADHZD AEGXH AENEX AENZO AFFNX AFPKN AFRAH AFYAG AHMBA AIAGR ALMA_UNASSIGNED_HOLDINGS ALUQC AMNDL AOIJS BAWUL BAYMD BCNDV CAG CIDKT CITATION CS3 CZ4 DIK DU5 D~K E3Z EBD EBS EMOBN F5P GROUPED_DOAJ GX1 H13 HH5 HYE HZ~ IH2 KAQDR KQ8 KSI OAWHX OBC OBS OEB OES OJQWA OVT P2P PEELM PQQKQ R44 RD5 RNS ROL ROZ RPM RXO SV3 TN5 TOX TR2 WG7 WOQ X7H XSB YSK ZKX ~91 ~D7 ~KM CGR CUY CVF ECM EIF ESTFP NPM 7X8 5PM
ID	FETCH-LOGICAL-c311t-d77b1b5ed57ab2599f5b547f5aebcb58f48a9b29d45e73f3b4573a077099e5df3
ISICitedReferencesCount	8
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000823445500001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	0305-1048 1362-4962
IngestDate	Tue Sep 30 16:23:51 EDT 2025 Fri Sep 05 08:20:04 EDT 2025 Sat Nov 01 14:17:05 EDT 2025 Sat Nov 29 04:15:09 EST 2025 Tue Nov 18 21:38:08 EST 2025
IsDoiOpenAccess	true
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Issue	13
Language	English
License	https://creativecommons.org/licenses/by/4.0 The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
LinkModel	OpenURL
MergedId	FETCHMERGED-LOGICAL-c311t-d77b1b5ed57ab2599f5b547f5aebcb58f48a9b29d45e73f3b4573a077099e5df3
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors are Joint First Authors. These authors are Joint Second Authors.
ORCID	0000-0001-6227-9850
OpenAccessLink	http://dx.doi.org/10.1093/nar/gkac545
PMID	35819193
PQID	2688569728
PQPubID	23479
PageCount	16
ParticipantIDs	pubmedcentral_primary_oai_pubmedcentral_nih_gov_9303390 proquest_miscellaneous_2688569728 pubmed_primary_35819193 crossref_citationtrail_10_1093_nar_gkac545 crossref_primary_10_1093_nar_gkac545
PublicationCentury	2000
PublicationDate	2022-07-22
PublicationDateYYYYMMDD	2022-07-22
PublicationDate_xml	– month: 07 year: 2022 text: 2022-07-22 day: 22
PublicationDecade	2020
PublicationPlace	England
PublicationPlace_xml	– name: England
PublicationTitle	Nucleic acids research
PublicationTitleAlternate	Nucleic Acids Res
PublicationYear	2022
Publisher	Oxford University Press
Publisher_xml	– name: Oxford University Press
References	Dirac (2022072200035905900_B17) 2003; 278 Batlle (2022072200035905900_B50) 2017; 23 Hill (2022072200035905900_B28) 2019; 51 Langerak (2022072200035905900_B14) 2007; 204 Guo (2022072200035905900_B42) 2003; 22 Wang (2022072200035905900_B20) 2019; 574 Yang (2022072200035905900_B56) 2015; 10 Rolink (2022072200035905900_B15) 1991; 10 Ceccaldi (2022072200035905900_B2) 2016; 17 Edmunds (2022072200035905900_B9) 2008; 30 Wojtaszek (2022072200035905900_B12) 2019; 178 Xie (2022072200035905900_B46) 2010; 107 Gallina (2022072200035905900_B52) 2021; 81 Krijger (2022072200035905900_B25) 2013; 43 Ran (2022072200035905900_B23) 2013; 8 Linder (2022072200035905900_B51) 2019; 26 Pilzecker (2022072200035905900_B6) 2017; 114 Chatterjee (2022072200035905900_B31) 2020; 117 Krijger (2022072200035905900_B43) 2011; 10 Jha (2022072200035905900_B37) 2018; 430 Chou (2022072200035905900_B22) 2010; 70 Williams (2022072200035905900_B38) 2012; 47 Walter (2022072200035905900_B30) 2015; 520 Zan (2022072200035905900_B27) 2012; 2 Ross (2022072200035905900_B10) 2005; 33 Hoege (2022072200035905900_B7) 2002; 419 Kanemaru (2022072200035905900_B35) 2017; 39 Zhuo (2022072200035905900_B36) 2018; 55 Yang (2022072200035905900_B41) 2017; 216 Voorwerk (2022072200035905900_B58) 2019; 25 Mailand (2022072200035905900_B8) 2013; 14 Ogi (2022072200035905900_B48) 2010; 37 Olive (2022072200035905900_B24) 2006; 1 Jansen (2022072200035905900_B26) 2006; 203 Tsui (2022072200035905900_B3) 2019; 35 Martín-Pardillos (2022072200035905900_B11) 2017; 130 Deans (2022072200035905900_B1) 2011; 11 Hicks (2022072200035905900_B45) 2010; 30 Wellenstein (2022072200035905900_B19) 2019; 572 Abbondanzo (2022072200035905900_B16) 1993 Kottemann (2022072200035905900_B4) 2013; 493 Doles (2022072200035905900_B57) 2010; 107 Mizutani (2022072200035905900_B40) 2004; 64 Xiang (2022072200035905900_B49) 2017; 543 Räschle (2022072200035905900_B5) 2008; 134 Jolly (2022072200035905900_B21) 1997; 25 Flach (2022072200035905900_B29) 2014; 512 Nayak (2022072200035905900_B34) 2020; 6 Thakar (2022072200035905900_B44) 2020; 11 Huang (2022072200035905900_B55) 2016; 6 Wit (2022072200035905900_B39) 2015; 43 Avkin (2022072200035905900_B32) 2006; 22 Richardson (2022072200035905900_B47) 2012; 30 Hampp (2022072200035905900_B33) 2016; 113 Bassett (2022072200035905900_B54) 2004; 64 Buoninfante (2022072200035905900_B18) 2018; 9 Sanders (2022072200035905900_B13) 2017; 292 Silverstein (2022072200035905900_B53) 2010; 465
References_xml	– volume: 37 start-page: 714 year: 2010 ident: 2022072200035905900_B48 article-title: Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells publication-title: Mol. Cell doi: 10.1016/j.molcel.2010.02.009 – volume: 134 start-page: 969 year: 2008 ident: 2022072200035905900_B5 article-title: Mechanism of replication-coupled DNA interstrand crosslink repair publication-title: Cell doi: 10.1016/j.cell.2008.08.030 – volume: 543 start-page: 573 year: 2017 ident: 2022072200035905900_B49 article-title: RNA m6A methylation regulates the ultraviolet-induced DNA damage response publication-title: Nature doi: 10.1038/nature21671 – volume: 30 start-page: 95 year: 2012 ident: 2022072200035905900_B47 article-title: Testicular cancer: a narrative review of the role of socioeconomic position from risk to survivorship publication-title: Urol. Oncol. doi: 10.1016/j.urolonc.2011.09.010 – volume: 64 start-page: 3144 year: 2004 ident: 2022072200035905900_B40 article-title: Extensive chromosomal breaks are induced by tamoxifen and estrogen in DNA repair-deficient cells publication-title: Cancer Res. doi: 10.1158/0008-5472.CAN-03-3489 – volume: 2 start-page: 1220 year: 2012 ident: 2022072200035905900_B27 article-title: Rev1 recruits ung to switch regions and enhances dU glycosylation for immunoglobulin class switch DNA recombination publication-title: Cell Rep. doi: 10.1016/j.celrep.2012.09.029 – volume: 465 start-page: 1039 year: 2010 ident: 2022072200035905900_B53 article-title: Structural basis for the suppression of skin cancers by DNA polymerase eta publication-title: Nature doi: 10.1038/nature09104 – volume: 55 start-page: 2506 year: 2018 ident: 2022072200035905900_B36 article-title: Translesion synthesis DNA polymerase kappa is indispensable for DNA repair synthesis in cisplatin exposed dorsal root ganglion neurons publication-title: Mol. Neurobiol. doi: 10.1007/s12035-017-0507-5 – volume: 25 start-page: 1913 year: 1997 ident: 2022072200035905900_B21 article-title: Rapid methods for the analysis of immunoglobulin gene hypermutation: application to transgenic and gene targeted mice publication-title: Nucleic Acids Res. doi: 10.1093/nar/25.10.1913 – volume: 64 start-page: 6469 year: 2004 ident: 2022072200035905900_B54 article-title: The role of DNA polymerase η in translesion synthesis past platinum-DNA adducts in human fibroblasts publication-title: Cancer Res. doi: 10.1158/0008-5472.CAN-04-1328 – volume: 43 start-page: 282 year: 2015 ident: 2022072200035905900_B39 article-title: Roles of PCNA ubiquitination and TLS polymerases κ and η in the bypass of methyl methanesulfonate-induced DNA damage publication-title: Nucleic Acids Res. doi: 10.1093/nar/gku1301 – volume: 10 start-page: 1051 year: 2011 ident: 2022072200035905900_B43 article-title: PCNA ubiquitination-independent activation of polymerase η during somatic hypermutation and DNA damage tolerance publication-title: DNA Repair (Amst.) doi: 10.1016/j.dnarep.2011.08.005 – volume: 8 start-page: 2281 year: 2013 ident: 2022072200035905900_B23 article-title: Genome engineering using the CRISPR-Cas9 system publication-title: Nat. Protoc. doi: 10.1038/nprot.2013.143 – volume: 512 start-page: 198 year: 2014 ident: 2022072200035905900_B29 article-title: Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells publication-title: Nature doi: 10.1038/nature13619 – volume: 11 start-page: 2147 year: 2020 ident: 2022072200035905900_B44 article-title: Ubiquitinated-PCNA protects replication forks from DNA2-mediated degradation by regulating okazaki fragment maturation and chromatin assembly publication-title: Nat. Commun. doi: 10.1038/s41467-020-16096-w – volume: 25 start-page: 920 year: 2019 ident: 2022072200035905900_B58 article-title: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial publication-title: Nat. Med. doi: 10.1038/s41591-019-0432-4 – volume: 22 start-page: 407 year: 2006 ident: 2022072200035905900_B32 article-title: p53 and p21 regulate error-prone DNA repair to yield a lower mutation load publication-title: Mol. Cell doi: 10.1016/j.molcel.2006.03.022 – volume: 23 start-page: 1124 year: 2017 ident: 2022072200035905900_B50 article-title: Cancer stem cells revisited publication-title: Nat. Med. doi: 10.1038/nm.4409 – volume: 430 start-page: 1577 year: 2018 ident: 2022072200035905900_B37 article-title: Structural basis for human DNA polymerase kappa to bypass cisplatin intrastrand cross-link (Pt-GG) lesion as an efficient and accurate extender publication-title: J. Mol. Biol. doi: 10.1016/j.jmb.2018.04.023 – volume: 39 start-page: 6 year: 2017 ident: 2022072200035905900_B35 article-title: DNA polymerase kappa protects human cells against MMC-induced genotoxicity through error-free translesion DNA synthesis publication-title: Genes Environ doi: 10.1186/s41021-016-0067-3 – volume: 203 start-page: 319 year: 2006 ident: 2022072200035905900_B26 article-title: Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice publication-title: J. Exp. Med. doi: 10.1084/jem.20052227 – volume: 6 start-page: eaaz7808 year: 2020 ident: 2022072200035905900_B34 article-title: Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability publication-title: Sci. Adv. doi: 10.1126/sciadv.aaz7808 – volume: 17 start-page: 337 year: 2016 ident: 2022072200035905900_B2 article-title: The fanconi anaemia pathway: new players and new functions publication-title: Nat. Rev. Mol. Cell Biol. doi: 10.1038/nrm.2016.48 – volume: 14 start-page: 269 year: 2013 ident: 2022072200035905900_B8 article-title: Regulation of PCNA-protein interactions for genome stability publication-title: Nat. Rev. Mol. Cell Biol. doi: 10.1038/nrm3562 – volume: 107 start-page: 20792 year: 2010 ident: 2022072200035905900_B46 article-title: Error-prone translesion synthesis mediates acquired chemoresistance publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.1011412107 – volume: 47 start-page: 140 year: 2012 ident: 2022072200035905900_B38 article-title: Replication-Independent repair of DNA interstrand crosslinks publication-title: Mol. Cell doi: 10.1016/j.molcel.2012.05.001 – volume: 574 start-page: 268 year: 2019 ident: 2022072200035905900_B20 article-title: Inducing and exploiting vulnerabilities for the treatment of liver cancer publication-title: Nature doi: 10.1038/s41586-019-1607-3 – volume: 107 start-page: 20786 year: 2010 ident: 2022072200035905900_B57 article-title: Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.1011409107 – volume: 114 start-page: E6875 year: 2017 ident: 2022072200035905900_B6 article-title: DNA damage tolerance in hematopoietic stem and progenitor cells in mice publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.1706508114 – volume: 26 start-page: R31 year: 2019 ident: 2022072200035905900_B51 article-title: Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond publication-title: Endocr. Relat. Cancer doi: 10.1530/ERC-18-0289 – start-page: 803 volume-title: Guide to Techniques in Mouse Development, Methods in Enzymology year: 1993 ident: 2022072200035905900_B16 article-title: 49]Derivation of embryonic stem cell lines doi: 10.1016/0076-6879(93)25052-4 – volume: 30 start-page: 1217 year: 2010 ident: 2022072200035905900_B45 article-title: Differential roles for DNA polymerases eta, zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links publication-title: Mol. Cell. Biol. doi: 10.1128/MCB.00993-09 – volume: 113 start-page: E4311 year: 2016 ident: 2022072200035905900_B33 article-title: DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.1605828113 – volume: 419 start-page: 135 year: 2002 ident: 2022072200035905900_B7 article-title: RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO publication-title: Nature doi: 10.1038/nature00991 – volume: 22 start-page: 6621 year: 2003 ident: 2022072200035905900_B42 article-title: Mouse rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis publication-title: EMBO J. doi: 10.1093/emboj/cdg626 – volume: 216 start-page: 3097 year: 2017 ident: 2022072200035905900_B41 article-title: DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress publication-title: J. Cell Biol. doi: 10.1083/jcb.201702006 – volume: 33 start-page: 1280 year: 2005 ident: 2022072200035905900_B10 article-title: Vertebrate DNA damage tolerance requires the C-terminus but not BRCT or transferase domains of REV1 publication-title: Nucleic Acids Res. doi: 10.1093/nar/gki279 – volume: 204 start-page: 1989 year: 2007 ident: 2022072200035905900_B14 article-title: A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification publication-title: J. Exp. Med. doi: 10.1084/jem.20070902 – volume: 493 start-page: 356 year: 2013 ident: 2022072200035905900_B4 article-title: Fanconi anaemia and the repair of watson and crick DNA crosslinks publication-title: Nature doi: 10.1038/nature11863 – volume: 520 start-page: 549 year: 2015 ident: 2022072200035905900_B30 article-title: Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells publication-title: Nature doi: 10.1038/nature14131 – volume: 178 start-page: 152 year: 2019 ident: 2022072200035905900_B12 article-title: A small molecule targeting mutagenic translesion synthesis improves chemotherapy publication-title: Cell doi: 10.1016/j.cell.2019.05.028 – volume: 10 start-page: 327 year: 1991 ident: 2022072200035905900_B15 article-title: Long-term proliferating early pre b cell lines and clones with the potential to develop to surface Ig-positive, mitogen reactive b cells in vitro and in vivo publication-title: EMBO J. doi: 10.1002/j.1460-2075.1991.tb07953.x – volume: 9 start-page: 18832 year: 2018 ident: 2022072200035905900_B18 article-title: Precision cancer therapy: profiting from tumor specific defects in the DNA damage tolerance system publication-title: Oncotarget doi: 10.18632/oncotarget.24777 – volume: 11 start-page: 467 year: 2011 ident: 2022072200035905900_B1 article-title: DNA interstrand crosslink repair and cancer publication-title: Nat. Rev. Cancer doi: 10.1038/nrc3088 – volume: 117 start-page: 28918 year: 2020 ident: 2022072200035905900_B31 article-title: REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks publication-title: Proc. Natl. Acad. Sci. U.S.A. doi: 10.1073/pnas.2016064117 – volume: 6 start-page: 19552 year: 2016 ident: 2022072200035905900_B55 article-title: Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck publication-title: Sci. Rep. doi: 10.1038/srep19552 – volume: 81 start-page: 442 year: 2021 ident: 2022072200035905900_B52 article-title: The ubiquitin ligase RFWD3 is required for translesion DNA synthesis publication-title: Mol. Cell doi: 10.1016/j.molcel.2020.11.029 – volume: 292 start-page: 10347 year: 2017 ident: 2022072200035905900_B13 article-title: Pharmacological targeting of RAD6 enzyme-mediated translesion synthesis overcomes resistance to platinum-based drugs publication-title: J. Biol. Chem. doi: 10.1074/jbc.M117.792192 – volume: 10 start-page: e0120334 year: 2015 ident: 2022072200035905900_B56 article-title: REV3L, a promising target in regulating the chemosensitivity of cervical cancer cells publication-title: PLoS One doi: 10.1371/journal.pone.0120334 – volume: 51 start-page: 1283 year: 2019 ident: 2022072200035905900_B28 article-title: DNA cross-link repair safeguards genomic stability during premeiotic germ cell development publication-title: Nat. Genet. doi: 10.1038/s41588-019-0471-2 – volume: 70 start-page: 440 year: 2010 ident: 2022072200035905900_B22 article-title: Drug combination studies and their synergy quantification using the chou-talalay method publication-title: Cancer Res. doi: 10.1158/0008-5472.CAN-09-1947 – volume: 1 start-page: 23 year: 2006 ident: 2022072200035905900_B24 article-title: The comet assay: a method to measure DNA damage in individual cells publication-title: Nat. Protoc. doi: 10.1038/nprot.2006.5 – volume: 43 start-page: 2765 year: 2013 ident: 2022072200035905900_B25 article-title: Rev1 is essential in generating g to c transversions downstream of the ung2 pathway but not the msh2+ung2 hybrid pathway publication-title: Eur. J. Immunol. doi: 10.1002/eji.201243191 – volume: 130 start-page: 1523 year: 2017 ident: 2022072200035905900_B11 article-title: Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions publication-title: Blood doi: 10.1182/blood-2017-01-764274 – volume: 35 start-page: 199 year: 2019 ident: 2022072200035905900_B3 article-title: The fanconi anemia pathway and fertility publication-title: Trends Genet. doi: 10.1016/j.tig.2018.12.007 – volume: 30 start-page: 519 year: 2008 ident: 2022072200035905900_B9 article-title: PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis in the avian cell line DT40 publication-title: Mol. Cell doi: 10.1016/j.molcel.2008.03.024 – volume: 278 start-page: 11731 year: 2003 ident: 2022072200035905900_B17 article-title: Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53 publication-title: J. Biol. Chem. doi: 10.1074/jbc.C300023200 – volume: 572 start-page: 538 year: 2019 ident: 2022072200035905900_B19 article-title: Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis publication-title: Nature doi: 10.1038/s41586-019-1450-6
SSID	ssj0014154
Score	2.4427369
Snippet	Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is...
SourceID	pubmedcentral proquest pubmed crossref
SourceType	Open Access Repository Aggregation Database Index Database Enrichment Source
StartPage	7420
SubjectTerms	Animals Cisplatin - therapeutic use DNA Damage DNA Repair DNA Replication DNA-Directed DNA Polymerase - metabolism Genome Integrity, Repair and Humans Mice Neoplasms - drug therapy Neoplasms - genetics Precision Medicine Proliferating Cell Nuclear Antigen - metabolism Ubiquitination
Title	Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine
URI	https://www.ncbi.nlm.nih.gov/pubmed/35819193 https://www.proquest.com/docview/2688569728 https://pubmed.ncbi.nlm.nih.gov/PMC9303390
Volume	50
WOSCitedRecordID	wos000823445500001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText	1
inHoldings	1
isFullTextHit
isPrint
journalDatabaseRights	– providerCode: PRVAON databaseName: DOAJ Directory of Open Access Journals customDbUrl: eissn: 1362-4962 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0014154 issn: 0305-1048 databaseCode: DOA dateStart: 20050101 isFulltext: true titleUrlDefault: https://www.doaj.org/ providerName: Directory of Open Access Journals – providerCode: PRVASL databaseName: Oxford Journals Open Access Collection customDbUrl: eissn: 1362-4962 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0014154 issn: 0305-1048 databaseCode: TOX dateStart: 19960101 isFulltext: true titleUrlDefault: https://academic.oup.com/journals/ providerName: Oxford University Press
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwtV3JbtswECWctEB7Kdqki7sYLBDk0EBItNAUj85i9BDYPTiAbwIpUbVTW3K9BMlP9Lv6WZ0hKdluckgPvQiGRIuy55kezsx7Q8iBkn6WC8m8KGXCi7Ig9xQTbS9UqfC10Foqo65_yXu9eDgU3xqN3xUX5mbCiyK-vRWz_2pqOAfGRursP5i7vimcgNdgdDiC2eH4KMOfjy1fHN1AY2ITa3XljOe9zlEmp1iosywnem4IA1bNGVksGsWUi7Lw9Az9ykrMtaJPTu6OLA_C8K1sEbnRc0CpAdurB6vIUj3fztlfVxxfeFS8ZTrOMFuxEUgz-XtZXEtpS-07k6ysL4zkyBaBF7LmFWUaw2blsqLJm4T_aV0ucrrCMHOOsMER_cl4OhtLpPMsFvCJ5nIz2hGYythgIwDqG5aXcCu4fuCcW9WtnG2F3nBjjeaRod_d__OwwloFFrZ3v_-QKbNCl9si3b1-0r26vEwGF8PB4eynh_3LMM_vmrnskCcBZwLX10F_WOezwE2y7ZXdkzqmKMx4DPMdu9m2faN7G56_63Y3HKHBS_LC7WBoxyLvFWnoYo_sdwq5LKd39JCammKTrNkjz86qfoL75FcFTFrm1ACTWmBSACYFYFILTFoDk1pgUgdMugVMCmaka2DSNTCpAyYFYNIamNQCk1bAfE2uuheDs6-e6wbipaHvL72Mc-UrpjPGpYJNu8iZYhHPmdQqVSzOo1gKFYgsYpqHeagixkN5wjnsgTTL8vAN2YXn1O8IhXcEyAn3URyR61zleZDBypQq8N6jQDbJl8oOSeqk8rFjyySxJRthAkZLnNGa5KAePLMKMQ8P-1wZNIEvHtNystDlapEE7ThmbcGDuEneWgPXN0J1QgF7rCbhW6avB6A6_PaVYjwyKvECnNNQnLx_xLwfyPP1b-0j2V3OV_oTeZreLMeLeYvs8GHcMsGqlkH1HzoE6YI
linkProvider	Oxford University Press
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Division+of+labor+within+the+DNA+damage+tolerance+system+reveals+non-epistatic+and+clinically+actionable+targets+for+precision+cancer+medicine&rft.jtitle=Nucleic+acids+research&rft.au=Spanjaard%2C+Aldo&rft.au=Shah%2C+Ronak&rft.au=de+Groot%2C+Dani%C3%ABl&rft.au=Buoninfante%2C+Olimpia+Alessandra&rft.date=2022-07-22&rft.issn=1362-4962&rft.eissn=1362-4962&rft.volume=50&rft.issue=13&rft.spage=7420&rft_id=info:doi/10.1093%2Fnar%2Fgkac545&rft.externalDBID=NO_FULL_TEXT
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0305-1048&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0305-1048&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0305-1048&client=summon