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The role of mismatch repair in DNA damage-induced apoptosis
1Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky Medical Center, Lexington 40536, USA. gmli@pop.uky.edu
Abstract:
DNA mismatch repair plays a critical role in maintaining genomic integrity. Defects in human mismatch repair are the primary cause of certain types of cancer, including hereditary nonpolyposis colorectal cancer. In the past, the ability of mismatch repair proteins to correct DNA mismatches that occur during DNA replication, repair, and recombination was considered the primary mechanism by which it contributes to genomic stability. However, increasing evidence supports the idea that the mismatch repair system also contributes to genome stability by stimulating DNA damage-induced apoptosis as part of the cytotoxic response to physical and chemical agents. MutS/MutL homologues mediate the process of apoptosis by binding to DNA adducts and either provoking futile repair events or blocking steps in DNA metabolism (i.e., DNA replication and/or repair). This damage recognition step by mismatch repair (MMR) proteins stimulates a signaling cascade for apoptosis, resulting in activation of protein kinase(s) that phosphorylate p53 and/or the related protein p73. Activated p53 and p73 in turn transmit a signal to the apoptotic machinery to execute cell death. The goal of this commentary is to discuss the molecular mechanism(s) by which mismatch repair proteins stimulate apoptosis.
Insights
DNA mismatch repair (MMR) proteins maintain genomic integrity and suppress cancer. Beyond DNA repair, MMR also triggers apoptosis in response to DNA damage, a crucial cytotoxic mechanism.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- DNA mismatch repair (MMR) is vital for genomic stability and preventing cancers like hereditary nonpolyposis colorectal cancer.
- Historically, MMR's role was seen solely in correcting DNA replication errors.
- Emerging evidence highlights MMR's function in inducing apoptosis following DNA damage.
Purpose of the Study:
- To explore the molecular mechanisms by which MMR proteins induce apoptosis.
- To elucidate MMR's dual role in maintaining genome stability.
Main Methods:
- The study is a commentary discussing existing evidence.
- Focuses on the molecular interactions of MutS/MutL homologues with DNA adducts.
- Examines the signaling cascade leading to apoptosis.
Main Results:
- MMR proteins bind DNA adducts, initiating futile repair or blocking DNA metabolism.
- This damage recognition triggers a signaling cascade involving protein kinases.
- The cascade leads to p53 and/or p73 phosphorylation, activating apoptosis.
Conclusions:
- MMR proteins actively contribute to genome stability by inducing programmed cell death (apoptosis).
- This apoptotic function is a key component of the cellular response to DNA damage.
- Understanding this mechanism is crucial for cancer therapy development.