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

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 oncogenic mechanism, which fosters genome instability and tumor cell growth in H3.3 mutant pHGG, thus opening 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.

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

“…It remains an open question as to why the tail domain mutants of H3.3 are spatially confined in a hindbrain tissue-specific manner. Surprisingly, the H3.3K27M mutant promotes CIN and induces NHEJ-mediated DNA damage response through the DNA end-processing enzyme Polynucleotide Kinase 3′-Phosphatase (PNKP) (Rondinelli et al, 2022). The rationale underlying the deposition of H3.3 mutants on stalled forks despite the presence of other canonical histones remains unclear.…”