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

Author:

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

Abstract

ABSTRACTThe 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 CRL1SKP2and CRL4CDT2in 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 CRL4AMBRA1-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.One-Sentence SummaryTo maintain genome stability, D-type cyclins limit mismatch repair (MMR) in G1, whereas their degradation is necessary for proper MMR function in S phase.

Publisher

Cold Spring Harbor Laboratory

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