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

Gergely Rona1, Bearach Miwatani-Minter2, Qingyue Zhang2

  • 1Department 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.

Molecular Cell
|March 8, 2024
PubMed

Insights

D-type cyclins and p21 inhibit DNA mismatch repair (MMR) in G0/G1 by preventing MMR protein binding to PCNA. Their degradation at G1/S allows MMR to function, preventing mutations and microsatellite instability.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • DNA Repair

Background:

  • Mismatch repair (MMR) corrects DNA replication errors but can be error-prone in G0/G1 phases.
  • Mechanisms controlling MMR activity during early cell cycle phases are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling DNA mismatch repair (MMR) during the G0 and G1 cell cycle phases.
  • To investigate the role of D-type cyclins and p21 in modulating MMR activity and its impact on genomic stability.

Main Methods:

  • Utilized mammalian cell culture models.
  • Investigated protein interactions using techniques such as co-immunoprecipitation and Western blotting.
  • Assessed DNA damage response and repair pathways.
  • Analyzed cell cycle progression and protein degradation dynamics.

Main Results:

  • D-type cyclins are recruited to oxidative DNA damage sites in a PCNA- and p21-dependent manner.
  • D-type cyclins stabilize p21, which then inhibits MMR proteins from binding to PCNA, thereby suppressing MMR.
  • This inhibition is independent of CDK4/CDK6 and conserved in G0/G1.
  • Degradation of D-type cyclins and p21 via cullin-RING ubiquitin ligase (CRL) at the G1/S transition restores MMR.
  • Sustained D-type cyclin expression during S-phase increases mutation rates and microsatellite instability.

Conclusions:

  • D-type cyclins and p21 act as key regulators, inhibiting MMR in G0/G1 to prevent potential errors.
  • The timely degradation of D-type cyclins and p21 is crucial for MMR activation at the G1/S transition, ensuring accurate DNA replication and genomic integrity.
  • Dysregulation of this pathway, particularly persistent D-type cyclin expression, contributes to increased mutagenesis and microsatellite instability.
Keywords:
AMBRA1CDK4D-type cyclinsDNA repairDNA repair pathway choiceG0 DNA repairG1 DNA repairPCNAbase excision repaircell cyclecullin-RING ubiquitin ligasescyclin D1genome stabilitymismatch repairoxidative DNA damage

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