한빛사논문
- 조회1,531
Jae Jin Kim1,5, Seo Yun Lee1,5, Ji-Hye Choi3, Hyun Goo Woo3,4, Blerta Xhemalce1,2, Kyle M. Miller1,2,6,*
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
2Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
3Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
4Department of Biomedical Science, Graduate School, Ajou University, Suwon 16499, Republic of Korea
5These authors contributed equally.
6Lead Contact
*Corresponding author
Abstract
Stabilization of stalled replication forks is a prominent mechanism of PARP (Poly(ADP-ribose) Polymerase) inhibitor (PARPi) resistance in BRCA-deficient tumors. Epigenetic mechanisms of replication fork stability are emerging but remain poorly understood. Here, we report the histone acetyltransferase PCAF (p300/CBP-associated) as a fork-associated protein that promotes fork degradation in BRCA-deficient cells by acetylating H4K8 at stalled replication forks, which recruits MRE11 and EXO1. A H4K8ac binding domain within MRE11/EXO1 is required for their recruitment to stalled forks. Low PCAF levels, which we identify in a subset of BRCA2-deficient tumors, stabilize stalled forks, resulting in PARPi resistance in BRCA-deficient cells. Furthermore, PCAF activity is tightly regulated by ATR (ataxia telangiectasia and Rad3-related), which phosphorylates PCAF on serine 264 (S264) to limit its association and activity at stalled forks. Our results reveal PCAF and histone acetylation as critical regulators of fork stability and PARPi responses in BRCA-deficient cells, which provides key insights into targeting BRCA-deficient tumors and identifying epigenetic modulators of chemotherapeutic responses.
논문정보
- Research article
- 2020년 09월 (BRIC 등록일 2020-09-29)
- 국내+국외 연구진
- 생명과학 > 분자생물학
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