Protein Lysine Lactylation in DNA Damage Response: Regulatory Mechanisms and Emerging Functions
TL;DR
Recent advances in understanding of lactylation in homologous recombination (HDR) and non-homologous end joining (NHEJ) and their roles in DNA repair and tumor chemoresistance are discussed.
Abstract
Genomic DNA is constantly exposed to endogenous and exogenous stresses that can cause different types of DNA damage. DNA double-strand breaks (DSBs) are among the most damaging forms of DNA lesions, as persistent breaks can compromise genome stability. In response to such damage, cells activate DNA damage response (DDR) pathways that detect lesions and promote their repair. Lysine lactylation (Kla), a recently identified lysine acylation modification, links cellular metabolism and DNA repair. Recent evidence suggests that Kla may influence DDR by modulating the stability, interactions, and activity of DNA repair proteins. This review discusses recent advances in our understanding of lactylation in homologous recombination (HDR) and non-homologous end joining (NHEJ). We focus on MRE11, NBS1, BLM, and XLF lactylation and their roles in DNA repair and tumor chemoresistance. These findings suggest that lactylation can affect genome stability, tumor progression, and responses to cancer therapy by regulating key DDR factors. However, how lactylation is regulated during DDR and how it affects DNA repair remain largely unclear. Further studies are needed to elucidate how DNA damage-induced lactylation can be regulated, the functions of lactylation writers and erasers, and the significance of lactylation in various disease contexts.