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Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse

Marijke van Oosten1, Gerdine J Stout, Claude Backendorf

  • 1Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.

DNA Repair
|November 10, 2004
PubMed

Insights

UVB radiation triggers DNA damage, leading to cell cycle arrest. Mismatch repair protein Msh2 is crucial for this S-phase arrest in mouse skin cells, suggesting a novel role for MMR in DNA repair signaling.

Area of Science:

  • Molecular Biology
  • Genetics
  • Dermatology

Background:

  • Nucleotide excision repair (NER), cell cycle regulation, and apoptosis are key defenses against UVB radiation's carcinogenic effects.
  • NER removes UVB-induced DNA photolesions through global genome repair (GGR) and transcription-coupled repair (TCR).
  • Previous studies noted UVB-induced tetraploid keratinocyte accumulation in Xpc(-/-) mice (lacking GGR), suggesting replication errors past photolesions and mismatch repair (MMR) involvement.

Purpose of the Study:

  • To investigate the role of the mismatch repair (MMR) protein Msh2 in UVB-induced cell cycle arrest.
  • To determine the specific phase of the cell cycle where the arrest occurs.
  • To elucidate the mechanism linking DNA repair pathways and cell cycle regulation following UVB exposure.

Main Methods:

  • Utilized Xpc(-/-)Msh2(-/-) mice and derived keratinocytes for in vivo and in vitro experiments.
  • Quantified UVB-induced arrested cells in Msh2-deficient and control groups.
  • Analyzed cell cycle progression using calyculin A-induced premature chromosome condensation (PCC) in cultured keratinocytes.

Main Results:

  • Msh2 deficiency significantly reduced the percentage of UVB-induced arrested cells (40-50% in vivo, 30-40% in vitro).
  • Premature chromosome condensation analysis revealed that the UVB-induced arrest occurs in late S phase, not G2 phase.
  • These findings implicate Msh2 in the S-phase arrest following UVB exposure in mouse epidermis and keratinocytes.

Conclusions:

  • The mismatch repair (MMR) protein Msh2 plays a significant role in the UVB-induced S-phase arrest in mouse skin cells.
  • This suggests that MMR is involved in the cellular response to UVB-induced DNA damage, potentially through signaling pathways.
  • The study highlights a novel function of MMR beyond DNA mismatch correction in the context of UV-induced genotoxicity and cell cycle control.

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