CDK-independent role of D-type cyclins in regulating DNA mismatch repair

Although mismatch repair (MMR) is essential for correcting DNA replication errors, it can also recognize other lesions, such as oxidized bases. In G0 and G1, MMR is kept in check through unknown mechanisms as it is error-prone during these cell cycle phases. We show that in mammalian cells, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins inhibit the proteasomal degradation of p21, which competes with MMR proteins for binding to PCNA, thereby inhibiting MMR. The ability of D-type cyclins to limit MMR is CDK4- and CDK6-independent and is conserved in G0 and G1. At the G1/S transition, the timely, cullin-RING ubiquitin ligase (CRL)-dependent degradation of D-type cyclins and p21 enables MMR activity to efficiently repair DNA replication errors. Persistent expression of D-type cyclins during S-phase inhibits the binding of MMR proteins to PCNA, increases the mutational burden, and promotes microsatellite instability. [Display omitted] •D-type cyclins are recruited to oxidative DNA lesions to inhibit MMR activity•This role is present in G0 and G1 and is independent of CDK4 and CDK6 activity•D-type cyclins’ degradation at G1/S ensures proper MMR activity during S-phase•Absence of D-type cyclins in S limits mutational burden and microsatellite instability Rona et al. show that D-type cyclins, critical for cell cycle progression, also regulate the choice of DNA repair pathways upon oxidative stress independently of their associated-kinase subunits. The presence of D-type cyclins in G0 and G1 and their absence in S-phase are essential for maintaining genome integrity by modulating MMR activity.