biostudies-literatureFuchs HANatural Science Foundation of WuhanDepartment of Pathology and Molecular Medicine, Queen's UniversityNatural Sciences and Engineering Research CouncilNational Natural Science Foundation of ChinaNCI NIH HHSOntario Institute of Cancer ResearchNIH HHSNIGMS NIH HHSgkaf1381https://www.ebi.ac.uk/biostudies/studies/S-EPMC12802913biostudies-literatureUnknown54(2)Mutations in the histone variant H3.3 have been discovered in pediatric and adult gliomas and osteosarcomas. One of these is G34R in the H3.3 N-terminal tail. While this mutation is known to disrupt epigenomic pathways, the effects on nucleosome structure itself have not been explored. In light of recent studies, which demonstrate that the interaction of the H3 tail with nucleosomal and linker DNA is driven in large part by arginine residues, we sought to determine if the G34R cancer mutation and adjacent G33R mutation, not observed in cancer, directly alter nucleosome structural dynamics. Using nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we investigate the effects of these mutations on the H3 tail in the context of the nucleosome. We show that both of theseNucleic acids researchG34R cancer mutation alters the conformational ensemble and dynamics of the histone H3.3 tails.PMC12802913P30 CA046934R35 GM128705R35GM128705CCNU25JC005S10 OD014010-01RGPIN/02972-2021122051122024040801020302Peng YRosas RMusselman CAFuchs HAZhang HAyyapan SPanchenko ARfalseG34R cancer mutation alters the conformational ensemble and dynamics of the histone H3.3 tails.Mutations in the histone variant H3.3 have been discovered in pediatric and adult gliomas and osteosarcomas. One of these is G34R in the H3.3 N-terminal tail. While this mutation is known to disrupt epigenomic pathways, the effects on nucleosome structure itself have not been explored. In light of recent studies, which demonstrate that the interaction of the H3 tail with nucleosomal and linker DNA is driven in large part by arginine residues, we sought to determine if the G34R cancer mutation and adjacent G33R mutation, not observed in cancer, directly alter nucleosome structural dynamics. Using nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we investigate the effects of these mutations on the H3 tail in the context of the nucleosome. We show that both of these2026-01-01T00:00:00Z2026 Jan2026-06-06T15:16:12.827Z2026-06-01T03:10:57.402ZS-EPMC128029134153358710.1093/nar/gkaf1381