Metabolites that accumulate in a tumour due to altered cancer metabolism can limit DNA repair. Now in Nature, lactate has been found to promote homologous recombination-mediated DNA repair and resistance to DNA-damaging chemotherapy.

As lactate enables lysine lactylation of proteins, the authors next analysed whether resistant tumours had altered lactylation, finding that global levels of lactylation were increased. As lactylated proteins were recruited to sites of DNA double-strand breaks (DSBs), the authors focused on lactylated DNA repair proteins, specifically NBS1, a protein central to DNA repair initiation. Lactate did not mediate cisplatin resistance in cells lacking NBS1, and both cisplatin and lactate treatment increased lactylation of NBS1. The authors identified K388 as the site for NBS1 lactylation and TIP60, a member of the MYST subfamily of histone acetyltransferases, as the lactyltransferase. Histone deacetylase 3 (HDAC3) was suggested as the NBS1 de-lactylase.