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...

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Published in:	Nucleic acids research Vol. 50; no. 13; pp. 7420 - 7435
Main Authors:	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
Language:	English
Published:	England Oxford University Press 22.07.2022
Subjects:	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 Access:	Get full text
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Summary:	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.
Bibliography:	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.
ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkac545