Inhibiting MRE11 lactylation for cancer

Targeting the homologous repair and end resection-promoting protein MRE11 by inhibiting its lactylation, a CREBBP-induced post-translational modification that promotes MRE11 DNA binding, could help treat cancer by decreasing DNA repair and increasing sensitivity to DNA damage response inhibitors and chemotherapy.

Bioinformatic analyses of public basal-like breast cancer datasets identified that high LDHA, an enzyme that promotes lactate production and protein lactylation via CREBBP, was correlated with higher homologous recombination in tumors expressing high BRCA1. Cell-based screening of key homologous recombination regulators identified MRE11 as highly lactylated compared with other homologous recombination regulators. ...