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Scientific article
Open access
English

H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

Published inNature communications, vol. 15, no. 1, 4430
Publication date2024-05-24
First online date2024-05-24
Abstract

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

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Keywords
  • Humans
  • BRCA1 Protein / metabolism
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / genetics
  • Histones / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • DNA Replication / drug effects
  • BRCA2 Protein / metabolism
  • BRCA2 Protein / genetics
  • BRCA2 Protein / deficiency
  • Cell Line, Tumor
  • Female
  • Drug Resistance, Neoplasm / genetics
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • DNA Breaks, Double-Stranded
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / drug therapy
  • Mice
  • Tumor Suppressor p53-Binding Protein 1 / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • DNA Repair
  • Carrier Proteins / metabolism
  • Carrier Proteins / genetics
  • DNA Damage
  • Rad51 Recombinase / metabolism
  • Rad51 Recombinase / genetics
Citation (ISO format)
DIBITETTO, Diego et al. H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. In: Nature communications, 2024, vol. 15, n° 1, p. 4430. doi: 10.1038/s41467-024-48715-1
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Article (Published version)
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Identifiers
ISSN of the journal2041-1723
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