DNA mismatch repair protein MSH2 (MSH2)

DNA mismatch repair protein MSH2 is a critical component of the post-replicative DNA mismatch repair (MMR) system, where it forms heterodimers with MSH6 (MutS alpha) or MSH3 (MutS beta) to identify and initiate the repair of base-base mismatches and insertion-deletion loops [1, 7]. As an ATPase of the MutS family, MSH2 acts as a molecular switch, using ATP binding and hydrolysis to coordinate the recruitment of downstream repair factors like MLH1 [1, 19, 38]. Mutations in the MSH2 gene are the leading cause of Lynch syndrome, an autosomal dominant condition that significantly increases the lifetime risk of colorectal, endometrial, and other cancers [8, 12, 15]. In the therapeutic landscape, MSH2 is primarily utilized as a biomarker; tumors with MSH2 deficiency (dMMR/MSI-H) exhibit high microsatellite instability and a high neoantigen burden, making them exceptionally responsive to immune checkpoint inhibitors such as pembrolizumab and dostarlimab [6, 14, 33]. Beyond its role in repair, MSH2 is involved in DNA damage-induced apoptosis and cell cycle signaling, and experimental research has identified small molecules that can directly bind MSH2 to trigger cell death or stabilize mutant forms of the protein [9, 28, 29].

Other names

MutS homolog 2hMSH2HNPCCHNPCC1COCA1FCC1LCFS2hMMRCS2MSH-2

MSH2 primarily serves as a clinical biomarker for immunotherapy; its deficiency (dMMR/MSI-H) leads to a high neoantigen burden, making tumors highly sensitive to immune checkpoint inhibitors like pembrolizumab and dostarlimab that target the PD-1/PD-L1 pathway [14, 33]. Experimental small molecules such as reserpine and evodiamine have been shown to directly bind MSH2, inducing a conformational change that triggers caspase-dependent apoptosis independently of DNA damage [28]. Furthermore, proteasome inhibitors like bortezomib can be used to stabilize certain unstable MSH2 missense variants, potentially restoring DNA repair function and chemosensitivity in specific genetic contexts [29].