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- W2942417292 abstract "PURPOSE: Approximately 20% of hemispheric pHGA have a mutation in the histone H3.3 encoding H3F3A gene, leading to a glycine-arginine substitution (H3.3G34R). However, our understanding of the biological consequences of this mutation remain poor. Here we use a novel proteomics-based strategy to investigate the H3.3G34R-associated changes in the histone interactome. METHOD: We utilized BioID to map the interactome of wildtype (WT) and G34R mutant Histone H3.3. The histones were expressed with an N-terminally tagged BirA* protein that ligates biotin to juxtaposed proteins. Biotinylated proteins were identified through mass spectrometry post biotin affinity capture. RESULTS: Through BioID we identified 343 proteins that had altered interaction with H3.3G34R vs WT H3.3 including histone modifiers/readers. Additionally, DNA repair protein involved in double stranded break (DSB) repair such as BRCA1 and RAD18 lost interaction with H3.3G34R. These findings were validated using Western blot of streptavidin pull downs and proximity ligation assay. To test for H3.3G34R-dependent defects in DSB repair, we generated immortalized normal human astrocytes (iNHAs) expressing H3.3G34R, empty vector (EV) or H3WT. H3.3G34R iNHAs had approximately double the number of yH2AX foci 1 and 24 hours post radiation compared to empty vector and WT control. H3.3G34R cells also had a larger olive tail moment based on the neutral comet assay suggesting a delay in DSB repair kinetics. Furthermore, cells expressing H3.3G34R accumulated 4216 more mutations including 342 indel events over six passages without the presence of an exogenous DNA damaging agent as determined by whole genome sequencing. CONCLUSION: H3.3G34R mutations leads to changes in interactome that suggest an altered function at the chromatin level. Our data suggest that H3.3G34R mutation is inducing genomic instability through loss of function in the DSB repair pathway and may provide a novel avenue of therapeutic vulnerability." @default.
- W2942417292 created "2019-05-03" @default.
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- W2942417292 date "2019-04-01" @default.
- W2942417292 modified "2023-09-23" @default.
- W2942417292 title "HGG-22. CHARACTERIZING THE ROLE H3.3G34R MUTATION IN PEDIATRIC HIGH GRADE ASTROCYTOMA" @default.
- W2942417292 doi "https://doi.org/10.1093/neuonc/noz036.116" @default.
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