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Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

ABSTRACT: Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism responds to and governs the loss-of-function oncohistone remains unclear. Here, we generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B level, disrupted cell divisions, and caused animal sterility. Our genetic screens identified mutations defective in a histone H3-H4 chaperone UNC-85 as suppressors that recovered H2B 3KO fertility. We found that unc-85 mutations reduced chromatin H3-H4 levels and that inhibiting other H3-H4 chaperones or H3-H4 histones also rescued H2B 3KO sterility. The oncohistone H2BE76K mutation disrupts the H2B-H4 interface and causes nucleosome instability, and we showed that blocking H3-H4 chaperones restored cell division defects in C. elegans or human cells carrying H2BE76K. Thus, our results indicate that reducing chromatin H3-H4 rescues H2B loss and suggest that inhibiting H3-H4 chaperones may be a therapeutic strategy to treat cancers resulting from loss-of-function H2B oncohistone.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE185582 | GEO | 2022/04/03

REPOSITORIES: GEO

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Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

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