Therapeutic targeting of the DNA mismatch repair pathway.
The mismatch repair (MMR) pathway is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. Mutations in four genes involved in MMR, MSH2, MLH1, PMS2 and MSH6, predispose to a range of tumorigenic conditions, including hereditary nonpolyposis colon cancer, also known as Lynch syndrome. Here we discuss the canonical MMR pathway and the burgeoning evidence for noncanonical roles for the MMR genes, and highlight the therapeutic implications of MMR. In particular, we discuss how the DNA repair defect in MMR-deficient cancers could be exploited by the development of novel therapeutic strategies based on synthetic lethal approaches.
Martin
Sarah A
SA
Cancer Research UK Gene Function and Regulation Group, The Institute of Cancer Research, London, United Kingdom.
Lord
Christopher J
CJ
Ashworth
Alan
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008495:Medical Oncology / Q000639:trends; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D057170:Translational Research, Biomedical / Q000639:trends
D000970:Antineoplastic Agents; D009687:Nuclear Proteins