Molecular Target Synopsis
Domains and Structures
Drugs and Clinical Candidates
Ligand Efficiency Plot
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
Germline Genetics

MSH2 (P43246) - Overview - Molecular Target Synopsis


MSH2, DNA mismatch repair protein Msh2
UniProt P43246

Also Known as MSH2_HUMAN, MSH2

Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Recruits DNA helicase MCM9 to chromatin which unwinds the mismatch containg DNA strand (PubMed:26300262). ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. In melanocytes may modulate both UV-B-induced cell cycle regulation and apoptosis. Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Heterodimer consisting of MSH2-MSH6 (MutS alpha) or MSH2-MSH3 (MutS beta) (PubMed:8942985). Both heterodimers form a ternary complex with MutL alpha (MLH1-PMS1) (PubMed:9788596, PubMed:10856833, PubMed:11427529, PubMed:11429708, PubMed:12414623, PubMed:14676842). Interacts with MCM9; the interaction recruits MCM9 to chromatin (PubMed:26300262). Interacts with MCM8 (PubMed:26300262). Interacts with EXO1 (PubMed:9788596, PubMed:10856833, PubMed:11427529, PubMed:11429708, PubMed:12414623, PubMed:14676842). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165). Interacts with ATR (PubMed:14657349). Interacts with SLX4/BTBD12; this interaction is direct and links MutS beta to SLX4, a subunit of different structure-specific endonucleases (PubMed:19596235). Interacts with SMARCAD1 (PubMed:18675275).

Inspect Structure
See all 3D Structures for MSH2

Isoforms / Transcripts (Protein Coding)

Sub-cellular localization

UniProt: MSH2 is active in the following subcellular-locations: chromosome, nucleus.
GO terms: MSH2 is active in the following subcellular-locations: membrane, mismatch repair complex, MutSalpha complex, MutSbeta complex, nuclear chromosome, nucleoplasm, nucleus.

GO terms

Gene Copy Number Variation

In COSMIC - Cell Lines Project MSH2 has gain in 3 cell-lines, loss in 2 cell-lines and no signal in 1000 cell-lines. (see details)

Gene Expression

In NCI60, the highest expressing cell lines are: K_562, SN12C, NCI_H522

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: TK, DMS 79, NCI-H187

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: MCF-7, NHLF, HeLa-S3

(see details)

3D Structures

For MSH2 there are:
9 structures (9 chains) solved
9 are solved in complex with at least one small molecule ligand

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry

MSH2 has been screened with compounds ( bioactivities). (see details)