Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors.
Nucleic Acids Res
; 52(5): 2372-2388, 2024 Mar 21.
Article
en En
| MEDLINE
| ID: mdl-38214234
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Encefálicas
/
Histonas
/
Glioma
Límite:
Child
/
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia