Exploring the Molecular Underpinnings of Cancer-Causing Oncohistone Mutants Using Yeast as a Model.
Exploring the Molecular Underpinnings of Cancer-Causing Oncohistone Mutants Using Yeast as a Model.
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DOI：
10.3390/jof9121187
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发表时间：
2023-12-11
期刊：
影响因子：
--
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理解癌症起始和进展的分子基础对于制定有效的治疗策略至关重要。最近，已经鉴定出编码驱动肿瘤发生的组蛋白的基因发生突变，这些关键蛋白质由此转变为“癌组蛋白”。癌组蛋白突变体通常是单一错义突变，要理解它们如何破坏组蛋白的正常功能以驱动肿瘤发生，就需要明确此类变化的功能影响。组蛋白基因在人类基因组中存在多个拷贝，有15个基因编码组蛋白H3异构体，到目前为止，大多数癌组蛋白变体都是针对这种组蛋白进行分析的。由于在癌组蛋白存在的情况下同时表达如此多的野生型组蛋白，可能很难解读突变蛋白的确切机制影响。与人类不同，芽殖酵母和裂殖酵母分别仅含有两个或三个组蛋白H3基因。此外，酵母组蛋白与人类H3蛋白具有约90%的序列同一性。其基因的简单性和进化保守性使酵母成为表征癌组蛋白的极佳模型。在酵母模型中还可以利用遗传学方法的优势来确定可作为可行治疗靶点的细胞信号通路。在这篇综述中，我们重点关注酵母模型作为一种发现工具的价值，它可以提供机制方面的见解，并为后续人类的转化研究提供信息。
Understanding the molecular basis of cancer initiation and progression is critical in developing effective treatment strategies. Recently, mutations in genes encoding histone proteins that drive oncogenesis have been identified, converting these essential proteins into “oncohistones”. Understanding how oncohistone mutants, which are commonly single missense mutations, subvert the normal function of histones to drive oncogenesis requires defining the functional consequences of such changes. Histones genes are present in multiple copies in the human genome with 15 genes encoding histone H3 isoforms, the histone for which the majority of oncohistone variants have been analyzed thus far. With so many wildtype histone proteins being expressed simultaneously within the oncohistone, it can be difficult to decipher the precise mechanistic consequences of the mutant protein. In contrast to humans, budding and fission yeast contain only two or three histone H3 genes, respectively. Furthermore, yeast histones share ~90% sequence identity with human H3 protein. Its genetic simplicity and evolutionary conservation make yeast an excellent model for characterizing oncohistones. The power of genetic approaches can also be exploited in yeast models to define cellular signaling pathways that could serve as actionable therapeutic targets. In this review, we focus on the value of yeast models to serve as a discovery tool that can provide mechanistic insights and inform subsequent translational studies in humans.
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影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
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
DOI：
10.1016/j.bbagrm.2021.194781
发表时间：
2022-01-06
影响因子：
4.7
作者：
Amigo, Roberto;Farkas, Carlos;Gutierrez, Jose L.
通讯作者：
Gutierrez, Jose L.
影响因子：
14.8
作者：
Bagert JD;Mitchener MM;Patriotis AL;Dul BE;Wojcik F;Nacev BA;Feng L;Allis CD;Muir TW
通讯作者：
Muir TW
影响因子：
3.3
作者：
Duina, Andrea A.;Miller, Mary E.;Keeney, Jill B.
通讯作者：
Keeney, Jill B.