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

Diego Dibitetto (), Martin Liptay, Francesca Vivalda, Hülya Dogan, Ewa Gogola, Martín González Fernández, Alexandra Duarte, Jonas A. Schmid, Morgane Decollogny, Paola Francica, Sara Przetocka, Stephen T. Durant, Josep V. Forment, Ismar Klebic, Myriam Siffert, Roebi Bruijn, Arne N. Kousholt, Nicole A. Marti, Martina Dettwiler, Claus S. Sørensen, Jean-Christophe Tille, Manuela Undurraga, Intidhar Labidi-Galy, Massimo Lopes, Alessandro A. Sartori, Jos Jonkers () and Sven Rottenberg ()
Additional contact information
Diego Dibitetto: University of Bern
Martin Liptay: University of Bern
Francesca Vivalda: University of Zürich
Hülya Dogan: University of Bern
Ewa Gogola: The Netherlands Cancer Institute
Martín González Fernández: University of Bern
Alexandra Duarte: The Netherlands Cancer Institute
Jonas A. Schmid: University of Zürich
Morgane Decollogny: University of Bern
Paola Francica: University of Bern
Sara Przetocka: University of Zürich
Stephen T. Durant: AstraZeneca
Josep V. Forment: AstraZeneca
Ismar Klebic: University of Bern
Myriam Siffert: University of Bern
Roebi Bruijn: The Netherlands Cancer Institute
Arne N. Kousholt: Oncode Institute
Nicole A. Marti: University of Bern
Martina Dettwiler: University of Bern
Claus S. Sørensen: University of Copenhagen
Jean-Christophe Tille: Hôpitaux Universitaires de Genève
Manuela Undurraga: Hôpitaux Universitaires de Genève
Intidhar Labidi-Galy: Swiss Cancer Center Leman
Massimo Lopes: University of Zürich
Alessandro A. Sartori: University of Zürich
Jos Jonkers: The Netherlands Cancer Institute
Sven Rottenberg: University of Bern

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48715-1

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