Cyclin D1 expression and cell cycle response in DNA mismatch repair-deficient cells upon methylation and UV-C damage

Exp Cell Res. 2004 Jan 1;292(1):123-34. doi: 10.1016/j.yexcr.2003.08.018.

Abstract

We have evaluated cell survival, apoptosis, and cell cycle responses in a panel of DNA mismatch repair (MMR)-deficient colon and prostate cancer cell lines after alkylation and UV-C damage. We show that although these MMR-deficient cells tolerate alkylation damage, they are as sensitive to UV-C-induced damage as are the MMR-proficient cells. MMR-proficient cells arrest in the S-G2 phase of the cell cycle and initiate apoptosis following alkylation damage, whereas MMR-deficient cells continue proliferation. However, two prostate cancer cell lines that are MMR-deficient surprisingly arrest transiently in S-G2 after alkylation damage. Progression through G1 phase initially depends on the expression of one or more of the D-type cyclins (D1, D2, and/or D3). Analysis of cyclin D1 expression shows an initial MMR-independent decrease in the protein level after alkylation as well as UV-C damage. At later time points, however, only DNA damage-arrested cells showed decreased cyclin D1 levels irrespective of MMR status, indicating that reduced cyclin D1 could be a result of a smaller fraction of cells being in G1 phase rather than a result of an intact MMR system. Finally, we show that cyclin D1 is degraded by the proteasome in response to alkylation damage.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / toxicity
  • Alkylation
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Base Pair Mismatch*
  • Cell Cycle* / drug effects
  • Cell Cycle* / radiation effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Cyclin D1 / metabolism*
  • Cysteine Endopeptidases / metabolism
  • DNA Damage / drug effects*
  • DNA Damage / genetics
  • DNA Damage / radiation effects*
  • DNA Methylation*
  • DNA Repair
  • DNA, Neoplasm / analysis
  • Humans
  • Male
  • Methylnitronitrosoguanidine / toxicity
  • Multienzyme Complexes / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Proteasome Endopeptidase Complex
  • Time Factors
  • Ultraviolet Rays / adverse effects

Substances

  • Alkylating Agents
  • DNA, Neoplasm
  • Multienzyme Complexes
  • Methylnitronitrosoguanidine
  • Cyclin D1
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex