Fatty acid oxidation facilitates DNA double-strand break repair by promoting PARP1 acetylation

DNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways have been correlated with cellular response to DNA damage. Here, we show that fatty acid oxidation (FAO) is a crucial regulator of DNA double-strand break repair, particularly homologous recombination repair. Mechanistically, FAO contributes to DNA repair by activating poly(ADP-ribose) polymerase 1 (PARP1), an enzyme that detects DNA breaks and promotes DNA repair pathway. Upon DNA damage, FAO facilitates PARP1 acetylation by providing acetyl-CoA, which is required for proper PARP1 activity. Indeed, cells reconstituted with PARP1 acetylation mutants display impaired DNA repair and enhanced sensitivity to DNA damage. Consequently, FAO inhibition reduces PARP1 activity, leading to increased genomic instability and decreased cell viability upon DNA damage. Finally, our data indicate that FAO serves as an important participant of cellular response to DNA damage, supporting DNA repair and genome stability.

Automated summary

DNA repair is a crucial stress response mechanism that is vital for maintaining genome integrity following DNA damage. Recent studies have shown that metabolic pathways are involved in the cellular response to DNA damage. In this study, the researchers demonstrate that fatty acid oxidation (FAO) plays a key role in DNA double-strand break repair, particularly in homologous recombination repair. They found that FAO activates poly(ADP-ribose) polymerase 1 (PARP1), an enzyme involved in DNA repair, by promoting PARP1 acetylation with acetyl-CoA. Inhibition of FAO leads to reduced PARP1 activity, increased genomic instability, and decreased cell viability in response to DNA damage. This study highlights the importance of FAO in cellular response to DNA damage and its role in supporting DNA repair and genome stability.