Mismatch repair endonuclease PMS2 (PMS2)

Mismatch repair endonuclease PMS2 is a key enzyme in the DNA mismatch repair (MMR) pathway that functions to recognize and correct base mispairings or small insertion/deletion loops occurring during DNA replication[1][2][3][7][9]. The protein forms a heterodimer with MLH1 (MutLα complex), which is essential for coordinating downstream repair events through its endonuclease and weak ATPase activities[1][3][7]. PMS2 is critical for maintaining genome integrity, preventing carcinogenesis, and modulating cell cycle arrest and apoptosis in response to DNA damage (including interactions with p53 and p73)[1][4][5]. Germline pathogenic variants in PMS2 are causative for hereditary cancer risk syndromes such as Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), with high tumor mutational burden serving as a biomarker for response to immune checkpoint inhibition in deficient tumors[1][2][5]. Due to its essential role in DNA repair, PMS2 is not directly targeted by drugs, but its deficiency status is a critical determinant for immunotherapy eligibility and prognosis in certain cancers[1][2][5].

Other names

PMS1 protein homolog 2DNA mismatch repair protein PMS2PMS-2PMS2CLPMSL2HNPCC4MLH4LYNCH4MMRCS4H_DJ0042M02.9

While there are no direct small molecule modulators approved, tumors deficient in PMS2 (i.e., mismatch repair deficient/MSI-high) display increased sensitivity to immune checkpoint inhibition (e.g., with pembrolizumab, nivolumab) due to the resulting high tumor mutational burden and increased neoantigen load, which facilitates anti-tumor immune responses.