A Review of MutSα and its Absence in Mismatch Repair Related Ovarian Carcinomas

Abstract

This review investigates the roles of microsatellite instability (MSI) and the DNA mismatch repair (MMR) pathway in ovarian carcinomas. MMR promotes genome stability post‐replication by repairing DNA mismatches; defective MMR (dMMR) leaves genomic errors that can cause MSI. To repair these mismatches, the MMR system employs two sets of proteins that form heterodimers: MutL Homolog 1 (MLH1) in complex with post meiotic segregation increased 2 (PMS2) and MutS Homolog 2 (MSH2) in complex with MutS Homolog 6 (MSH6). The MSH2/MSH6 heterodimer (MutSα) recognizes the mismatch, while the MLH1/PMS2 heterodimer (MutLα) repairs the mismatch. The MSH2/MSH6 proteins are each composed of 5 asymmetrical structural domains, the first being responsible for mismatch binding, followed by the connector, lever, clamp, and ATPase domains, or domains I‐V, respectively. The MSH2 mismatch binding domain associates directly with DNA and extends a helix to block the polymerase, while MSH6 associates with DNA via its Phe‐X‐Glu motif. The MutSα complex has two states: an ADP‐bound state in which it searches for mismatches, and an ATP‐bound state in which it signals for repair. Lack of effective repair can contribute to carcinogenesis including ovarian carcinogenesis. Mismatches in microsatellites are phenotypic evidence that the MMR pathway is non‐functional in these tumors, and differences in MMR status are observed across ovarian carcinoma subtypes. For example MSH6 deficiency is associated with three subtypes of ovarian cancer: clear cell, mucinous, and endometrioid carcinomas, and there is a higher survival rate for patients with these MSH6 deficient tumors. Tumor MMR status also influences treatment efficacy and age of disease onset. Interestingly, only in familial carcinomas was MSI demonstrated as a supportive diagnostic tool. Tumors with high MSI can be treated with immunotherapy and immune checkpoint inhibitors; therefore investigating the MMR pathway functionality and MSI status of ovarian carcinomas can shape the course of treatment and patient outcomes.