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

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 stud...

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Published in:	Nature communications Vol. 15; no. 1; pp. 4430 - 14
Main Authors:	Dibitetto, Diego, Liptay, Martin, Vivalda, Francesca, Dogan, Hülya, Gogola, Ewa, González Fernández, Martín, Duarte, Alexandra, Schmid, Jonas A., Decollogny, Morgane, Francica, Paola, Przetocka, Sara, Durant, Stephen T., Forment, Josep V., Klebic, Ismar, Siffert, Myriam, de Bruijn, Roebi, Kousholt, Arne N., Marti, Nicole A., Dettwiler, Martina, Sørensen, Claus S., Tille, Jean-Christophe, Undurraga, Manuela, Labidi-Galy, Intidhar, Lopes, Massimo, Sartori, Alessandro A., Jonkers, Jos, Rottenberg, Sven
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 24.05.2024 Nature Publishing Group Nature Portfolio
Subjects:	45/47 45/91 49 631/337/151/2356 631/67/1059/2326 64 64/60 82/51 96 96/63 Adenosine diphosphate Animals Ataxia Telangiectasia Mutated Proteins - genetics Ataxia Telangiectasia Mutated Proteins - metabolism BRCA1 protein BRCA1 Protein - deficiency BRCA1 Protein - genetics BRCA1 Protein - metabolism BRCA2 Protein - deficiency BRCA2 Protein - genetics BRCA2 Protein - metabolism Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Carrier Proteins - genetics Carrier Proteins - metabolism Cell Line, Tumor Chemoresistance Damage Degradation Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded DNA Damage DNA Repair DNA Replication - drug effects Double-strand break repair Drug Resistance, Neoplasm - genetics Female Histone H2A Histones Histones - metabolism Homology Humanities and Social Sciences Humans Inhibitors Mice Mice, Nude multidisciplinary Poly(ADP-ribose) Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Replication Replication forks Ribose Science Science (multidisciplinary) Stability Tumor Suppressor p53-Binding Protein 1 - genetics Tumor Suppressor p53-Binding Protein 1 - metabolism Tumors
ISSN:	2041-1723, 2041-1723
Online Access:	Get full text
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Summary:	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. Histone H2AX has a known role in DNA damage repair but interestingly, its loss is associated with resistance to poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-deficient tumours. Here, the authors identify a role of γH2AX in the degradation of replication forks and demonstrate that H2AX loss drives PARP inhibitor resistance via increased stressed fork stability in BRCA-deficient tumours.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-48715-1