Defining the Role of the Histone 3.3 (H3.3G34R) Mutation in the Pathogenesis of Pediatric High Grade Astrocytoma
Year: 2020
Type: dissertation
Abstract: Pediatric high-grade astrocytoma (pHGG) is the leading cause of brain tumour related death in children. Approximately 15% of hemispheric pHGG have a mutations in the H3F3A gene, leading to a glycine-arginine substitution (H3.3G34R). A novel proteomics-based strategy, BioID, to investigate the H3.3G34R-associated changes in the histone interactome. H3.3G34R mutation lead to alterations in the histone H3.3 interactome including chromatin modifiers and DNA repair proteins. Expression of H3.3G34R in normal human astrocytes increased sensitivity to radiation and a delayed double stranded break repair kinetics as determined by neutral comet assay. H3.3G34R lead to loss of homologous recombination specific RAD51 recruitment in response to radiation and a compensation through the error prone 53BP1 specific non-homologous end joining pathway. Our data suggest that H3.3G34R mutation leads to dysregulation of the histone code and may induce genomic instability through loss of function in the DSB repair pathway and may provide a novel avenue of therapeutic vulnerability.
Source: TSpace (University of Toronto)
Author: Byungjin Kim
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3177858622