Human MutS alpha complex (hMutSα) (hMutSα)

The human MutS alpha (hMutSα) complex is a protein heterodimer composed of MSH2 and MSH6 that plays a central role in the DNA mismatch repair (MMR) pathway. It primarily functions by recognizing base-base mismatches and short insertion/deletion loops that occur during DNA replication (PubMed: 18226606). Beyond its role in maintaining genomic integrity, hMutSα is a critical mediator of the cytotoxic effects of certain chemotherapeutic agents, such as thiopurines (e.g., 6-thioguanine) and alkylating agents (e.g., temozolomide). When thiopurines are incorporated into DNA and subsequently methylated to form S6-methylthioguanine, hMutSα recognizes the resulting 6-MeTG:T or 6-MeTG:C mismatches (PubMed: 9159119, 11507052). This recognition triggers a futile repair cycle or direct signaling that leads to DNA double-strand breaks and apoptosis. Consequently, loss of hMutSα function through mutations or epigenetic silencing is a major driver of microsatellite instability-high (MSI-H) cancers and confers resistance to these specific classes of chemotherapy (PubMed: 15173044).

Other names

MSH2-MSH6 heterodimerMutS alphaHuman MutS homolog alphaMismatch repair complex alphaMSH2/MSH6 complex

Recognition of DNA mismatches and chemically modified bases (such as S6-methylthioguanine or O6-methylguanine), followed by the recruitment of hMutL alpha to initiate DNA excision or signal for programmed cell death.