Deciphering Allosteric Modulation of Cancer-Associated Histone Missense Mutations

Histone mutations have been implicated in various cancers, but their mechanistic effects on chromatin dynamics remain largely unexplored. In this study, we investigated allosteric modulation effects induced by 40 cancer-associated histone missense mutations. By combining computational approaches with experimental evidence, we assessed the allosteric and functional impact of these mutations. Our results reveal that the allosteric effects of histone mutations are position-specific, with mutations near the H3 and H4 histone N-terminal tails exhibiting the strongest long-range perturbations. Notably, we predicted seven mutations with significant allosteric effects, potentially altering nucleosome interactions. Experimental verification of H2BS64Y and H2BS64F mutations demonstrated that they disrupted normal histone function, altered H2BK120 ubiquitination levels and genome stability, findings suggestive of their potential carcinogenic effects. Collectively, these results show that allostery may serve as a critical mechanism underlying the oncogenic potential of some histone mutations, highlighting the need for further exploration of allosteric pathways in cancer epigenetics.