A Saccharomyces cerevisiae model and screen to define the functional consequences of oncogenic histone missense mutations.
A Saccharomyces cerevisiae model and screen to define the functional consequences of oncogenic histone missense mutations.
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DOI：
10.1093/g3journal/jkac120
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发表时间：
2022-07-06
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影响因子：
--
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Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in mammals as mutations occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histone H3.3 gene, despite the human genome encoding 15 H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leveraged the budding yeast model, which contains only 2 H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. Analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36 mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine-sensitive growth of H3K36-mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, including Esa1, a histone H4/H2A acetyltransferase; Tos4, a forkhead-associated domain-containing gene expression regulator; Pho92, an N6-methyladenosine RNA-binding protein; and Sgv1/Bur1, a cyclin-dependent kinase. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine-sensitive growth of H3K36R-mutant cells while the previously characterized binding interactions of Tos4 and Pho92 are not required for suppression. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.
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影响因子：
16.6
作者：
Justin N;Zhang Y;Tarricone C;Martin SR;Chen S;Underwood E;De Marco V;Haire LF;Walker PA;Reinberg D;Wilson JR;Gamblin SJ
通讯作者：
Gamblin SJ
DOI：
10.1016/j.jbc.2021.100533
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Cooke SL;Soares BL;Müller CA;Nieduszynski CA;Bastos de Oliveira FM;de Bruin RAM
通讯作者：
de Bruin RAM
影响因子：
4.6
作者：
Gao C;Bourke E;Scobie M;Famme MA;Koolmeister T;Helleday T;Eriksson LA;Lowndes NF;Brown JA
通讯作者：
Brown JA
影响因子：
11.5
作者：
Cidado, Justin;Boiko, Scott;Drew, Lisa
通讯作者：
Drew, Lisa
影响因子：
2.6
作者：
HILL, JE;MYERS, AM;TZAGOLOFF, A
通讯作者：
TZAGOLOFF, A