biostudies-literatureUnknown11(13)Pena-Gomez MJApurinic/apyrimidinic (AP) sites and single-strand breaks arising from base excision repair (BER) during the misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination-deficient (HRD) cells. At templated AP sites, cross-links between the DNA and 5-hydroxymethylcytosine binding, embryonic stem cell-specific (HMCES) regulate replication fork speed, avoiding cytotoxic double-strand breaks. While the role of HMCES at the template DNA strand is well studied, its effects on nascent DNA are not. We provide evidence that HMCES-DNA-protein cross-links (DPCs) are detrimental to the BER-mediated removal of 5-hydroxymethyl-2'-deoxycytidine (5hmdC)-derived 5-hydroxymethyl-2'-deoxyuridine from replication forks. HRD cells have heightened HMCES-DPCs, which iScience advanceseads3227https://www.ebi.ac.uk/biostudies/studies/S-EPMC11939059biostudies-literatureHMCES corrupts replication fork stability during base excision repair in homologous recombination-deficient cells.PMC11939059Berrada SReyes JCWijesekara Hanthi YRosado IVRodriguez-Martin YCostanzo VFreire RDel Rio Oliva MMasson JYPena-Gomez MJfalseHMCES corrupts replication fork stability during base excision repair in homologous recombination-deficient cells.Apurinic/apyrimidinic (AP) sites and single-strand breaks arising from base excision repair (BER) during the misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination-deficient (HRD) cells. At templated AP sites, cross-links between the DNA and 5-hydroxymethylcytosine binding, embryonic stem cell-specific (HMCES) regulate replication fork speed, avoiding cytotoxic double-strand breaks. While the role of HMCES at the template DNA strand is well studied, its effects on nascent DNA are not. We provide evidence that HMCES-DNA-protein cross-links (DPCs) are detrimental to the BER-mediated removal of 5-hydroxymethyl-2'-deoxycytidine (5hmdC)-derived 5-hydroxymethyl-2'-deoxyuridine from replication forks. HRD cells have heightened HMCES-DPCs, which i2025-01-01T00:00:00Z2025 Mar2025-06-28T03:05:27.389Z2025-06-28T03:05:27.389ZS-EPMC119390594013842310.1126/sciadv.ads3227