DNA mismatch repair protein Mlh1 (MLH1)

DNA mismatch repair protein Mlh1 (MLH1) is an enzyme encoded by the MLH1 gene on chromosome 3 that plays a central role in the recognition and repair of base pair mismatches arising during DNA replication and recombination[1][3]. It operates primarily as a component of the MutLα complex, acting downstream in the mismatch repair cascade by interacting with other proteins (including PMS2, MLH3, MSH2, and MSH6) to facilitate excision and repair of mismatched DNA[1]. Loss-of-function mutations, epigenetic silencing, or loss of MLH1 protein cause microsatellite instability and are the predominant molecular cause of Lynch syndrome (hereditary nonpolyposis colorectal cancer)[1][4]. MLH1 also helps regulate replication fork stability and suppresses replicative stress, especially in the context of BRCA2-deficient breast cancers[2]. MLH1-deficient tumors exhibit high mutation rates and improved response to immune checkpoint inhibitors due to increased neoantigen load. Germline mutations in MLH1 are diagnostic for hereditary cancer syndromes and guide personalized therapy selection[1][2][3].

Other names

MutL protein homolog 1COCA2HNPCCFCC2HNPCC2MLH-1LYNCH2MMRCS1hMLH1colon cancer nonpolyposis type 2

Drugs do not target MLH1 directly, but MLH1 deficiency causes high mutational burden and microsatellite instability. These features lead to increased neoantigen generation and better response to immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) in mismatch repair-deficient cancers[1][2].