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

Humans BRCA1 Protein / metabolism Histones / metabolism Poly(ADP-ribose) Polymerase Inhibitors / pharmacology DNA Replication / drug effects BRCA2 Protein / metabolism Cell Line, Tumor Female Drug Resistance, Neoplasm / genetics Animals Ataxia Telangiectasia Mutated Proteins / metabolism DNA Breaks, Double-Stranded Breast Neoplasms / genetics Mice Tumor Suppressor p53-Binding Protein 1 / metabolism DNA Repair Carrier Proteins / metabolism DNA Damage Rad51 Recombinase / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
24 May 2024
Historique:
received: 20 03 2024
accepted: 10 05 2024
medline: 25 5 2024
pubmed: 25 5 2024
entrez: 24 5 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-48715-1 PMID: 38789420
pubmed: 38789420
doi: 10.1038/s41467-024-48715-1
pii: 10.1038/s41467-024-48715-1
doi:

Substances chimiques

BRCA1 Protein 0
Histones 0
Poly(ADP-ribose) Polymerase Inhibitors 0
BRCA2 Protein 0
H2AX protein, human 0
BRCA1 protein, human 0
BRCA2 protein, human 0
Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1
Tumor Suppressor p53-Binding Protein 1 0
Carrier Proteins 0
ATR protein, human EC 2.7.11.1
TP53BP1 protein, human 0
Rad51 Recombinase EC 2.7.7.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

4430

Subventions

Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 883877
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 31BL30_189698
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 310030_208143
Organisme : Krebsliga Schweiz (Ligue Suisse Contre le Cancer)
ID : KFS_5519-02-2022
Organisme : Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)
ID : 2019.069.1

Informations de copyright

© 2024. The Author(s).

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Auteurs

Diego 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.
ORCID: 0000-0002-9549-5258

Martin 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.

Francesca Vivalda (F)

Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
ORCID: 0009-0008-5300-1505

Hülya 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.

Ewa Gogola (E)

Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
Oncode Institute, Amsterdam, The Netherlands.

Martín 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.
ORCID: 0009-0006-8308-5493

Alexandra Duarte (A)

Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
Oncode Institute, Amsterdam, The Netherlands.

Jonas A Schmid (JA)

Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
ORCID: 0000-0003-1791-1874

Morgane 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.
ORCID: 0009-0004-2426-3101

Paola 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.

Sara Przetocka (S)

Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.

Stephen T Durant (ST)

DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK.

Josep V Forment (JV)

DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK.

Ismar Klebic (I)

Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.

Myriam Siffert (M)

Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.

Roebi de Bruijn (R)

Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
Oncode Institute, Amsterdam, The Netherlands.

Arne N Kousholt (AN)

Oncode Institute, Amsterdam, The Netherlands.
Biotech Research and Innovation Centre, University of Copenhagen, 2200 N, Copenhagen, Denmark.
ORCID: 0000-0002-3972-1740

Nicole A 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.

Martina Dettwiler (M)

Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.

Claus S Sørensen (CS)

Biotech Research and Innovation Centre, University of Copenhagen, 2200 N, Copenhagen, Denmark.
ORCID: 0000-0001-6022-9710

Jean-Christophe Tille (JC)

Division of Clinical Pathology, Department of Diagnostics, Hôpitaux Universitaires de Genève, Geneva, Switzerland.

Manuela Undurraga (M)

Division of Gynecology, Department of Pediatrics and Gynecology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.

Intidhar 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.
ORCID: 0000-0002-0824-3475

Massimo Lopes (M)

Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
ORCID: 0000-0003-3847-8133

Alessandro A Sartori (AA)

Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
ORCID: 0000-0003-2770-0333

Jos 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.
ORCID: 0000-0002-9264-9792

Sven 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.
ORCID: 0000-0003-2044-9844

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéine BRCA1 › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Inhibiteurs de poly(ADP-ribose) polymérases › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Phénomènes génétiques › Réplication de l'ADN › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéine BRCA2 › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Eucaryotes › Animaux › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Protéines mutées dans l'ataxie-télangiectasie › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Cassures de l'ADN › Cassures double-brin de l'ADN › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Protéine-1 liant le suppresseur de tumeur p53 › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Phénomènes génétiques › Réparation de l'ADN › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › H2AX promotes replication fork degradation and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines des groupes de complémentation de l'anémie de Fanconi › Rad51 Recombinase › H2AX promotes replication fork degradation and...