D-type cyclins regulate DNA mismatch repair in the G1 and S phases of the cell cycle, maintaining genome stability.

Autor:	Rona G; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.; Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY 10016, USA., Miwatani-Minter B; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Zhang Q; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Goldberg HV; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Kerzhnerman MA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Howard JB; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Simoneschi D; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Lane E; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Hobbs JW; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Sassani E; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Wang AA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Keegan S; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA., Laverty DJ; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Piett CG; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Pongor LS; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.; Hungarian Centre of Excellence for Molecular Medicine, University of Szeged, Szeged, H-6728, Hungary., Xu ML; Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Andrade J; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Thomas A; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Sicinski P; Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.; Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, Chalubinskiego 5, 02-004 Warsaw, Poland., Askenazi M; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Biomedical Hosting LLC, 33 Lewis Avenue, Arlington, MA 02474, USA., Ueberheide B; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA., Fenyö D; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA., Nagel ZD; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Pagano M; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.; Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY 10016, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 13. Date of Electronic Publication: 2024 Jan 13.
DOI:	10.1101/2024.01.12.575420
Abstrakt:	The large majority of oxidative DNA lesions occurring in the G1 phase of the cell cycle are repaired by base excision repair (BER) rather than mismatch repair (MMR) to avoid long resections that can lead to genomic instability and cell death. However, the molecular mechanisms dictating pathway choice between MMR and BER have remained unknown. Here, we show that, during G1, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins shield p21 from its two ubiquitin ligases CRL1 SKP2 and CRL4 CDT2 in a CDK4/6-independent manner. In turn, p21 competes through its PCNA-interacting protein degron with MMR components for their binding to PCNA. This inhibits MMR while not affecting BER. At the G1/S transition, the CRL4 AMBRA1 -dependent degradation of D-type cyclins renders p21 susceptible to proteolysis. These timely degradation events allow the proper binding of MMR proteins to PCNA, enabling the repair of DNA replication errors. Persistent expression of cyclin D1 during S-phase increases the mutational burden and promotes microsatellite instability. Thus, the expression of D-type cyclins inhibits MMR in G1, whereas their degradation is necessary for proper MMR function in S. Competing Interests: Declaration of interests PS has been a consultant for Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, Cedilla Therapeutics, Syros Pharmaceuticals, Exo Therapeutics, Curie Bio Operations, Exscientia, Ligature Therapeutics, Redesign Science, Blueprint and Merck; his laboratory receives research funding from Novartis. MP is a scientific cofounder of SEED Therapeutics; receives research funding from and is a shareholder in Kymera Therapeutics; and is a consultant for, a member of the scientific advisory board of, and has financial interests in CullGen, SEED Therapeutics, Triana Biomedicines, and Umbra Therapeutics; however, no research funds were received from these entities, and the findings presented in this manuscript were not discussed with any person in these companies. The other authors have no competing interests to declare.
Databáze:	MEDLINE
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