# MSH2

## Overview
The MSH2 gene encodes the mutS homolog 2 protein, a pivotal component of the DNA mismatch repair (MMR) system, which is essential for maintaining genomic stability by correcting replication errors. As a member of the mutS family of proteins, MSH2 forms heterodimers with MSH6 or MSH3, creating the MutSα and MutSβ complexes, respectively. These complexes are responsible for recognizing and initiating the repair of mismatched DNA bases and insertion-deletion loops. The MSH2 protein is characterized by its ATPase activity, which is crucial for its function in DNA repair and interaction with other proteins involved in cell cycle control and apoptosis. Mutations in the MSH2 gene are strongly associated with Lynch syndrome, a hereditary condition that significantly increases the risk of colorectal and other cancers (Acharya1996hMSH2; Vasen2001MSH2; Edelbrock2013Structural).

## Structure
The MSH2 protein is a crucial component of the DNA mismatch repair system, forming a heterodimer known as MutSα with MSH6. This complex is essential for recognizing and initiating the repair of mismatched DNA bases. Structurally, MSH2 and MSH6 are divided into five conserved domains: the DNA mismatch binding domain, a connector domain, a lever domain, a clamp region for nonspecific DNA contact, and an ATPase domain for adenosine binding and hydrolysis (Edelbrock2013Structural). The ATPase domains, which are conserved helix-turn-helix motifs, are vital for the dimerization and function of the MutSα complex, forming two ATPase sites that stabilize the interface even without ATP binding (Edelbrock2013Structural).

The MSH2 protein also interacts with Holliday junctions, forming stable complexes that influence the conformation of these DNA structures (Alani1997Saccharomyces). MSH2 can bind in various oligomeric states, including monomers, dimers, trimers, and higher-order oligomers, which suggests a flexible quaternary structure (Alani1997Saccharomyces). The protein's ability to recognize both mismatched bases and Holliday junctions highlights its versatile role in DNA repair and recombination (Alani1997Saccharomyces).

## Function
The MSH2 gene encodes a protein that is a critical component of the DNA mismatch repair (MMR) system, which is essential for maintaining genomic stability by correcting errors that occur during DNA replication. In healthy human cells, MSH2 forms heterodimers with either MSH6 or MSH3. The MSH2/MSH6 complex, known as MutSα, primarily recognizes and repairs single base mismatches and small insertion-deletion loops, while the MSH2/MSH3 complex, MutSβ, targets larger insertion-deletion loops (Seifert2006The; Gammie2007Functional).

MSH2 is involved in several cellular processes beyond mismatch repair, including cell cycle control and apoptosis. It plays a role in activating cell cycle checkpoints, such as the S-phase checkpoint in response to DNA damage, by facilitating the phosphorylation of checkpoint kinases like CHK2 through interactions with ATM (Seifert2006The; Brown2002The). MSH2 is also implicated in DNA damage signaling pathways, contributing to cell cycle arrest and apoptosis when DNA damage is detected (Edelbrock2013Structural).

The protein is primarily active in the nucleus, where it interacts with other proteins to maintain genomic integrity and prevent the accumulation of mutations that could lead to cancer (Diouf2011Somatic; Seifert2006The).

## Clinical Significance
Mutations in the MSH2 gene are primarily associated with Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), which is the most common form of hereditary colorectal cancer. Individuals with MSH2 mutations have a significantly increased lifetime risk of developing colorectal cancer, with males having nearly a 100% risk by age 70, and females also facing a significant risk of endometrial cancer (Nagy2004Highly; Vasen2001MSH2). MSH2 mutations are also linked to a higher risk of other cancers, including those of the urinary tract, stomach, ovary, and brain, although these associations are not always statistically significant (Vasen2001MSH2).

In the Ashkenazi Jewish population, a specific founder mutation, MSH2*1906G→C, has been identified as a significant cause of Lynch syndrome. This mutation results in a substitution of proline for alanine at codon 636 and is associated with a wide range of cancers, including colorectal and endometrial cancers (Foulkes2002The). The mutation is linked to microsatellite instability, a hallmark of Lynch syndrome, due to the deficiency in DNA mismatch repair (Foulkes2002The). 

Alterations in MSH2 expression or interactions can lead to microsatellite instability, contributing to tumorigenesis (Renkonen2003Altered). The presence of large deletions and other genomic rearrangements in the MSH2 gene can also play a role in cancer susceptibility (Renkonen2003Altered).

## Interactions
The human MSH2 protein is a crucial component of the DNA mismatch repair (MMR) system, forming specific complexes with other proteins to facilitate DNA repair. MSH2 interacts with MSH6 and MSH3 to form the MutSα and MutSβ complexes, respectively. These complexes are responsible for recognizing and binding to DNA mismatches and insertion-deletion loops, initiating the repair process (Acharya1996hMSH2). MSH2 also forms a complex with MLH1, known as MutLα, which is essential for MMR signaling and repair (Mendillo2005Analysis).

The interaction between MSH2 and MSH6 is particularly significant, as it involves ATP binding and hydrolysis, which are necessary for the formation of a stable sliding clamp that can dissociate from mismatched DNA. This process is regulated by magnesium, which coordinates ATP processing (Heinen2011Human). MSH2 can also form a homomultimer complex, although MSH3 and MSH6 do not interact with themselves or each other (Acharya1996hMSH2).

Additionally, MSH2 interacts with other proteins through SHIP box motifs, as identified in human nuclear proteins. These interactions include those with SMARCAD1 and WDHD1, which are involved in DNA replication and repair processes (Goellner2018Identification).


## References


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[12. (Heinen2011Human) Christopher D. Heinen, Jennifer L. Cyr, Christopher Cook, Nidhi Punja, Miho Sakato, Robert A. Forties, Juana Martin Lopez, Manju M. Hingorani, and Richard Fishel. Human msh2 (hmsh2) protein controls atp processing by hmsh2-hmsh6. Journal of Biological Chemistry, 286(46):40287–40295, November 2011. URL: http://dx.doi.org/10.1074/jbc.m111.297523, doi:10.1074/jbc.m111.297523. This article has 29 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m111.297523)

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