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DNA Damage and Cellular Stress Responses

Potential Role of MLH1 in the Induction of p53 and Apoptosis by Blocking Transcription on Damaged DNA Templates¹

¹ Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School and ² Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI

Requests for reprints: Mats Ljungman, Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Medical School, 4306 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0936. Phone: (734) 764-3330; Fax: (734) 647-9654. E-mail: ljungman{at}umich.edu

Defects in DNA mismatch repair (MMR) are common in human cancers, confer tolerance to certain types of chemotherapeutic agents, and lead to genomic instability. In addition to their mismatch-correcting roles during DNA replication, MMR proteins can bind to certain DNA lesions and signal p53 and apoptosis by an unknown mechanism. To further study the mechanism by which the MMR protein MLH1 is involved in the induction of p53 and apoptosis, we exposed the colon carcinoma cell line HCT116 (MLH1-deficient) and mlh1-corrected HCT116 sublines to alkylating agents or hydrogen peroxide (H₂O₂). It was found that while alkylating agents induced both apoptosis and phosphorylation of the Ser-15 site of p53 in a MLH1-dependent manner, induction of apoptosis, but not p53 phosphorylation, was MLH1 dependent following treatment with H₂O₂. The MLH1-dependent induction of p53 phosphorylation by alkylating agents did not appear to be cell cycle dependent, arguing against a futile repair mechanism operating during S phase as the sole mechanism for the MLH1-dependent DNA damage signaling. Importantly, we found that both alkylating agents and H₂O₂ caused significant inhibition of mRNA synthesis in MLH1-expressing but not in MLH1-deficient cells. These findings suggest a novel mechanism of MLH1 in the induction p53 and apoptosis by inhibiting RNA polymerase II-dependent transcription on damaged DNA templates.

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