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PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.
- Source :
-
Molecular cell [Mol Cell] 2020 Oct 15; Vol. 80 (2), pp. 327-344.e8. Date of Electronic Publication: 2020 Sep 22. - Publication Year :
- 2020
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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.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Acetylation drug effects
Amino Acid Sequence
Ataxia Telangiectasia Mutated Proteins metabolism
BRCA1 Protein metabolism
BRCA2 Protein metabolism
Breast Neoplasms genetics
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic drug effects
Humans
Lysine metabolism
Models, Biological
Mutation genetics
Phosphorylation drug effects
Phosphoserine metabolism
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Protein Binding drug effects
p300-CBP Transcription Factors chemistry
p300-CBP Transcription Factors genetics
BRCA1 Protein deficiency
BRCA2 Protein deficiency
DNA Repair Enzymes metabolism
DNA Replication drug effects
Exodeoxyribonucleases metabolism
Histones metabolism
MRE11 Homologue Protein metabolism
p300-CBP Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 80
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 32966758
- Full Text :
- https://doi.org/10.1016/j.molcel.2020.08.018