PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells

Mol Cell. 2020 Oct 15;80(2):327-344.e8. doi: 10.1016/j.molcel.2020.08.018. Epub 2020 Sep 22.

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.

Keywords: BRCA1 and BRCA2; DNA replication stress; EXO1; MRE11; PARP; PCAF; acetylation; bromodomain; replication fork stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation / drug effects
  • Amino Acid Sequence
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / deficiency*
  • BRCA2 Protein / metabolism
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • DNA Repair Enzymes / metabolism*
  • DNA Replication* / drug effects
  • Exodeoxyribonucleases / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histones / metabolism*
  • Humans
  • Lysine / metabolism
  • MRE11 Homologue Protein / 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
  • p300-CBP Transcription Factors / metabolism*

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Histones
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Phosphoserine
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • EXO1 protein, human
  • Exodeoxyribonucleases
  • MRE11 Homologue Protein
  • DNA Repair Enzymes
  • Lysine