Abasic site processing protein HMCES (HMCES)

Abasic site processing protein HMCES (HMCES) is a highly conserved DNA repair enzyme that functions as a guardian of genome stability. Its mechanism involves covalent cross-linking to abasic (AP) sites—locations in DNA where base loss has occurred—thus shielding these vulnerable sites from cleavage by endonucleases and mutagenic translesion DNA polymerases[1][2][4][5]. This "suicide enzyme" action is mediated by its N-terminal SRAP domain, forming a thiazolidine linkage via an invariant cysteine (C2)[1][5]. HMCES is critical at stalled replication forks and during physiological recombination in B cells: in the immune system, it enables DNA double-strand break repair through the microhomology-mediated alternative end-joining (Alt-EJ) pathway during antibody class switch recombination, and suppresses deletions in immunoglobulin genes during somatic hypermutation[1][3][4][5]. HMCES is removed from DNA after cross-linking primarily through ubiquitin-mediated proteolysis or, context-dependently, by SPRTN protease[2]. Lack of HMCES causes increased DNA deletions, defects in antibody diversification, and genomic instability, pointing to disease relevance in immunodeficiency and potentially in cancer[1][4][3]. To date, no drugs directly target HMCES, but its roles in DNA repair and immunity make it an emerging target of interest in genome maintenance and cancer biology.

Other names

C3orf37DC12ES cell-specific 5hmC-binding proteinSRAPD1Embryonic stem cell-specific 5-hydroxymethylcytosine-binding proteinPeptidase HMCESSRAP domain-containing protein 1SOS response associated peptidase domain containing 1UPF0361 protein C3orf37Putative endonuclease HMCES

Covalent crosslink formation with DNA abasic sites via its SRAP domain to prevent mutagenic processing and dsDNA breaks[1][2][4][5]. Regulation of DNA repair pathway choice at replication forks and DSB sites (microhomology-mediated alternative end-joining)[1][3][4].