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

Gergely Rona1,2,3, Bearach Miwatani-Minter1,2, Qingyue Zhang1,2

  • 1Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.

Biorxiv : the Preprint Server for Biology
|January 23, 2024
PubMed

Insights

D-type cyclins inhibit mismatch repair (MMR) in G1 phase by stabilizing p21, preventing DNA damage. Their degradation at G1/S transition is crucial for MMR to repair replication errors, maintaining genomic stability.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • DNA Repair

Background:

  • Oxidative DNA damage in G1 is primarily repaired by base excision repair (BER), not mismatch repair (MMR), to prevent genomic instability.
  • The molecular mechanisms governing the choice between BER and MMR pathways remain largely unknown.

Approach:

  • Investigated the role of D-type cyclins, PCNA, p21, and ubiquitin ligases in regulating DNA repair pathway choice during the G1 phase.
  • Utilized cell cycle synchronization and molecular biology techniques to elucidate the interplay between these factors at sites of DNA damage.

Key Points:

  • D-type cyclins recruit to oxidative DNA damage sites in G1, protecting p21 from degradation by CRL1SKP2 and CRL4CDT2.
  • p21 binding to PCNA inhibits MMR, while BER remains unaffected.
  • Degradation of D-type cyclins at the G1/S transition allows p21 proteolysis, enabling MMR protein binding to PCNA for replication error repair.

Conclusions:

  • D-type cyclins act as critical regulators, inhibiting MMR in G1 phase to prioritize BER for oxidative DNA lesions.
  • The timely degradation of D-type cyclins is essential for activating MMR at the G1/S transition, ensuring accurate DNA replication.
  • Dysregulation of cyclin D1 expression during S-phase can lead to increased mutations and microsatellite instability.

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