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

Autor: Dibitetto D; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland. diego.dibitetto@marionegri.it.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland. diego.dibitetto@marionegri.it.; Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milan, Italy. diego.dibitetto@marionegri.it., Liptay M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland., Vivalda F; Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland., Dogan H; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland., Gogola E; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., González Fernández M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland., Duarte A; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Schmid JA; Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland., Decollogny M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland., Francica P; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland., Przetocka S; Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland., Durant ST; DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK., Forment JV; DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK., Klebic I; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland., Siffert M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland., de Bruijn R; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Kousholt AN; Oncode Institute, Amsterdam, The Netherlands.; Biotech Research and Innovation Centre, University of Copenhagen, 2200 N, Copenhagen, Denmark., Marti NA; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland., Dettwiler M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland., Sørensen CS; Biotech Research and Innovation Centre, University of Copenhagen, 2200 N, Copenhagen, Denmark., Tille JC; Division of Clinical Pathology, Department of Diagnostics, Hôpitaux Universitaires de Genève, Geneva, Switzerland., Undurraga M; Division of Gynecology, Department of Pediatrics and Gynecology, Hôpitaux Universitaires de Genève, Geneva, Switzerland., Labidi-Galy I; Faculty of Medicine, Department of Medicine and Center of Translational Research in Onco-Hematology, University of Geneva, Swiss Cancer Center Leman, Geneva, Switzerland.; Department of Oncology, Hôpitaux Universitaires de Genève, 4, Rue Gabrielle Perret-Gentil, Geneva, 1205, Switzerland., Lopes M; Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland., Sartori AA; Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland., Jonkers J; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands. j.jonkers@nki.nl.; Oncode Institute, Amsterdam, The Netherlands. j.jonkers@nki.nl., Rottenberg S; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland. sven.rottenberg@unibe.ch.; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland. sven.rottenberg@unibe.ch.; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands. sven.rottenberg@unibe.ch.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 May 24; Vol. 15 (1), pp. 4430. Date of Electronic Publication: 2024 May 24.
DOI: 10.1038/s41467-024-48715-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: