Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors
Giulia Giacomini, Sandra Piquet, Odile Chevallier, Juliette Dabin, Siau‐Kun Bai, Byungjin Kim, Robert Siddaway, Brian Raught, Étienne Coyaud, Chun‐Min Shan, Robert J. D. Reid, Takenori Toda, Rodney Rothstein, Viviana Barra, Therese Wilhelm, Sabah Hamadat, Chloé Bertin, Alexander Crane, Frank Dubois, Ignasi Forné, Axel Imhof, Pratiti Bandopadhayay, Rameen Beroukhim, Valeria Naim, Songtao Jia, Cynthia Hawkins, Beatrice Rondinelli, Sophie E. Polo
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.