JAE JIN KIM, Ph.D. Hallym University

PCAF promotes R-loop resolution by recruiting MRE11 and EXO1 through histone H4 acetylation

Genome stability is importance for maintaining cellular functions and preventing diseases. Histone acetylation, a process regulated by the histone acetyltransferase PCAF (p300/CBP-associated factor), plays a significant role in influencing genome stability. Interestingly, the expression of PCAF is downregulated in various cancers, such as colon, breast, ovary, and acute myeloid leukemia. However, the specific involvement of PCAF in transcription-mediated endogenous DNA damage remains elusive. To address this gap in knowledge, our study aims to investigate the effects of depleting PCAF on genome stability and its relationship with R-loop formation and resolution. We revealed that depletion of PCAF leads to the generation of R-loops, which are hybrid structures consisting of DNA-RNA that pose a threat to genome stability. Remarkably, the formation of these R-loops is dependent on the transcription process. Mechanistically, we discovered that PCAF facilitates histone H4K8 acetylation at the sites of R-loop formation, thereby recruiting MRE11 and EXO1 proteins. Intriguingly, MRE11 and EXO1 interact directly with H4K8ac and resolve R-loop formation independently of their nuclease activity. These findings reveal a novel mechanism in which PCAF-mediated histone acetylation, and nuclease proteins collaborate to resolve R-loops and safeguard genome stability. Understanding the regulation of R-loop formation and resolution is highly significant due to their implications in various human diseases, including cancer and neurodegenerative disorders. Consequently, our study provides new insights into the molecular mechanisms governing R-loop dynamics and highlights the essential role of PCAF in preserving genome stability.