Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors-Reference-Cited by-同舟云学术

Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors

Published:2024-01-12 Issue: Volume: Page:
ISSN:0305-1048
Container-title:Nucleic Acids Research
language:en
Short-container-title:

Author:

Giacomini Giulia¹,Piquet Sandra¹,Chevallier Odile¹,Dabin Juliette¹,Bai Siau-Kun¹,Kim Byungjin²,Siddaway Robert²,Raught Brian³⁴,Coyaud Etienne³⁴⁵,Shan Chun-Min⁶^ORCID,Reid Robert J D⁷^ORCID,Toda Takenori⁶,Rothstein Rodney⁷⁸,Barra Viviana⁹,Wilhelm Therese⁹,Hamadat Sabah⁹,Bertin Chloé⁹,Crane Alexander¹⁰,Dubois Frank¹⁰,Forne Ignasi¹¹^ORCID,Imhof Axel¹¹,Bandopadhayay Pratiti¹²,Beroukhim Rameen¹⁰,Naim Valeria⁹^ORCID,Jia Songtao⁶^ORCID,Hawkins Cynthia²^ORCID,Rondinelli Beatrice¹,Polo Sophie E¹^ORCID

Affiliation:

1. Epigenetics & Cell Fate Centre, CNRS/Université Paris Cité , Paris , France

2. Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children , Toronto , Canada

3. Princess Margaret Cancer Centre, University Health Network , 101 College Street , Toronto , ON M5G 1L7 , Canada

4. Department of Medical Biophysics, University of Toronto , Toronto , Canada

5. Université de Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM , F-59000 Lille , France

6. Department of Biological Sciences, Columbia University , New York , NY 10027 , USA

7. Department of Genetics & Development, Columbia University Irving Medical Center , New York , NY 10032 , USA

8. Department of Systems Biology, Columbia University Irving Medical Center , New York , NY 10032 , USA

9. CNRS UMR9019 Genome Integrity and Cancers, Université Paris-Saclay, Gustave Roussy Institute , Villejuif , France

10. Department of Medical Oncology, Dana-Farber Cancer Institute , Boston , USA

11. Protein Analysis Unit, BioMedical Center, Faculty of Medicine, Ludwig-Maximilians-University , Martinsried , Germany

12. Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center , Boston , USA

Abstract

Abstract Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme polynucleotide kinase 3′-phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.

Funder

National Institutes of Health

Deutsche Forschungsgemeinschaft

Gray Matters Brain Cancer Foundation and the Brown Fund for Innovation in Cancer Informatics

European Research Council

Canadian Cancer Society Research Institute

Canadian Institutes of Health Research

French National Research Agency

Labex ‘Who am I?’

Fondation pour la Recherche Medicale

Publisher

Oxford University Press (OUP)