Cyclin D1 expression and cell cycle response in DNA mismatch repair-deficient cells upon methylation and UV-C damage.
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.
Lützen
Anne
A
Department of Life Sciences and Chemistry, Roskilde University, 4000 Roskilde, Denmark.
Bisgaard
Hanne Cathrine
HC
Rasmussen
Lene Juel
LJ
D000477:Alkylating Agents / Q000633:toxicity; D000478:Alkylation; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D020137:Base Pair Mismatch; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D019175:DNA Methylation; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D009097:Multienzyme Complexes / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D009097:Multienzyme Complexes; D008769:Methylnitronitrosoguanidine; D019938:Cyclin D1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex