HMCES (5-hydroxymethylcytosine binding, ES cell specific) is a sensor and protector of abasic sites in single-stranded DNA that preserves genome integrity through error-free repair mechanisms 1. The protein recognizes abasic sites at replication forks and forms a stable thiazolidine covalent cross-link with DNA via its N-terminal catalytic cysteine 12. This cross-linking protects abasic sites from mutagenic translesion synthesis polymerases and error-prone endonucleases that would otherwise generate mutations and double-strand breaks 1. HMCES can self-reverse its thiazolidine cross-link in double-stranded DNA, enabling downstream repair by APEX1, or the cross-link can be degraded by the SPRTN metalloprotease 345. HMCES plays specialized roles in B-cell immunology: during somatic hypermutation, it suppresses deletions by cross-linking abasic sites while maintaining antigen-specific antibody production 6. Additionally, HMCES safeguards hematopoietic stem cells during stress responses by protecting against oxidative DNA damage-induced abasic sites 7. Clinical significance is highlighted by dysregulation in acute lymphoblastic leukemia associated with poor outcomes 7. HMCES dysfunction also contributes to genomic instability in homologous recombination-deficient tumors 8. Recent studies identify HMCES as a potential therapeutic target in drug-resistant chr3 myeloid leukemia 9.