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

Autor:	Spanjaard A; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Shah R; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., de Groot D; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Buoninfante OA; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Morris B; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Lieftink C; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Pritchard C; Intervention unit of the Mouse Clinic for Cancer and Aging research (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Zürcher LM; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Ormel S; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Catsman JJI; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., de Korte-Grimmerink R; Intervention unit of the Mouse Clinic for Cancer and Aging research (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Siteur B; Intervention unit of the Mouse Clinic for Cancer and Aging research (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Proost N; Intervention unit of the Mouse Clinic for Cancer and Aging research (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Boadum T; NKI Animal facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., van de Ven M; Intervention unit of the Mouse Clinic for Cancer and Aging research (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Song JY; Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Kreft M; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., van den Berk PCM; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Beijersbergen RL; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Jacobs H; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2022 Jul 22; Vol. 50 (13), pp. 7420-7435.
DOI:	10.1093/nar/gkac545
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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