AI Article Synopsis
- Pediatric high-grade gliomas (pHGG) are really tough brain tumors that usually can't be cured and often have mutations in a gene called histone H3.3.
- These mutations cause problems with how genes work and can make the brain cells unstable.
- Researchers found that a DNA repair enzyme called PNKP helps the cancer cells survive, which could be a new way to create treatments specifically for these mutated cells.
Article 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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10954481 | PMC |
| http://dx.doi.org/10.1093/nar/gkad1257 | DOI Listing |
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