H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 4430 |
| Tidsskrift | Nature Communications |
| Vol/bind | 15 |
| Antal sider | 14 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We wish to thank Hana Hanzlikova and Lea Lingg for critical reading of the manuscript. We thank all the members of the Rottenberg lab for helpful discussion. We thank Horizon Discovery for performing and analysing the CRISPR-Cas9 screens in SW620, HT29 and BT549 cells. We thank Daniel Durocher for sharing RPE1-hTERT TP53 -/- and RPE1- hTERT TP53 -/- ;BRCA1 -/- cells. We are grateful to Georgina Hayoz and Fabiana Steck for their support at the Vetsuisse Faculty mouse facility. We thank Denise Howald, Therese Waldburger, Cristina Graham Martinez, Aliaksandra Kakoinchankava, Valentine Dubois for technical assistance. Financial support came from the Swiss National Science Foundation (320030M_219453 to S.R. and J.J., 31BL30_189698 to S.R., 310030_208143 to A.A.S.), the European Union (ERC-2019-AdG-883877 to S.R.), the Swiss Cancer League (KFS-5519-02-2022 to S.R.), the ISREC foundation, the Boehringer Ingelheim Fonds (PhD fellowship to M.L.), the UZH Candoc Grant (no. FK-23-050 to F.V.), the Wilhelm Sander Foundation (no. 2019.069.1 to S.R.), and the Office of the Assistant Secretary of Defense for Health Affairs through the Ovarian Cancer Research Program under Award No. (W81XWH-22-1-0557 and W81XWH-22-1-0558 to S.R. and I.L.-G.). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. Figures\u00A01 a, 1 d, 2b, and supplementary fig.\u00A05d were created with Biorender.
Funding Information:
We wish to thank Hana Hanzlikova and Lea Lingg for critical reading of the manuscript. We thank all the members of the Rottenberg lab for helpful discussion. We thank Horizon Discovery for performing and analysing the CRISPR-Cas9 screens in SW620, HT29 and BT549 cells. We thank Daniel Durocher for sharing RPE1-hTERT TP53 and RPE1- hTERT TP53;BRCA1 cells. We are grateful to Georgina Hayoz and Fabiana Steck for their support at the Vetsuisse Faculty mouse facility. We thank Denise Howald, Therese Waldburger, Cristina Graham Martinez, Aliaksandra Kakoinchankava, Valentine Dubois for technical assistance. Financial support came from the Swiss National Science Foundation (320030M_219453 to S.R. and J.J., 31BL30_189698 to S.R., 310030_208143 to A.A.S.), the European Union (ERC-2019-AdG-883877 to S.R.), the Swiss Cancer League (KFS-5519-02-2022 to S.R.), the ISREC foundation, the Boehringer Ingelheim Fonds (PhD fellowship to M.L.), the UZH Candoc Grant (no. FK-23-050 to F.V.), the Wilhelm Sander Foundation (no. 2019.069.1 to S.R.), and the Office of the Assistant Secretary of Defense for Health Affairs through the Ovarian Cancer Research Program under Award No. (W81XWH-22-1-0557 and W81XWH-22-1-0558 to S.R. and I.L.-G.). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. Figures a, d, , and supplementary fig. were created with Biorender.
Publisher Copyright:
© The Author(s) 2024.
ID: 395024962