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

Gergely Rona; Bearach Miwatani-Minter; Qingyue Zhang; Hailey V Goldberg; Marc A Kerzhnerman; Jesse B Howard; Daniele Simoneschi; Ethan Lane; John W Hobbs; Elizabeth Sassani; Andrew A Wang; Sarah Keegan; Daniel J Laverty; Cortt G Piett; Lorinc S Pongor; Miranda Li Xu; Joshua Andrade; Anish Thomas; Piotr Sicinski; Manor Askenazi; Beatrix Ueberheide; David Fenyö; Zachary D Nagel; Michele Pagano

doi:10.1101/2024.01.12.575420

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

bioRxiv [Preprint]. 2024 Jan 13:2024.01.12.575420. doi: 10.1101/2024.01.12.575420.

Authors

Gergely Rona^{1

2

3}, Bearach Miwatani-Minter^{1

2}, Qingyue Zhang^{1

2}, Hailey V Goldberg^{1

2}, Marc A Kerzhnerman^{1

2}, Jesse B Howard^{1

2}, Daniele Simoneschi^{1

2}, Ethan Lane^{1

2}, John W Hobbs^{1

2}, Elizabeth Sassani^{1

2}, Andrew A Wang^{1

2}, Sarah Keegan^{1

2

4}, Daniel J Laverty⁵, Cortt G Piett⁵, Lorinc S Pongor^{6

7}, Miranda Li Xu⁸, Joshua Andrade^{1

2}, Anish Thomas⁶, Piotr Sicinski^{8

9}, Manor Askenazi^{1

10}, Beatrix Ueberheide^{1

2}, David Fenyö^{1

2

4}, Zachary D Nagel⁵, Michele Pagano^{1

2

3}

Affiliations

¹ Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
² Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA.
³ Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁴ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁵ Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁶ Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Hungarian Centre of Excellence for Molecular Medicine, University of Szeged, Szeged, H-6728, Hungary.
⁸ Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
⁹ Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, Chalubinskiego 5, 02-004 Warsaw, Poland.
¹⁰ Biomedical Hosting LLC, 33 Lewis Avenue, Arlington, MA 02474, USA.

Abstract

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.

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