Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail.
Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail.
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DOI：
10.7554/elife.65369
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发表时间：
2021-02-01
期刊：
影响因子：
7.7
通讯作者：
Partridge JF
中科院分区：
文献类型：
--
作者：
Lowe BR;Yadav RK;Henry RA;Schreiner P;Matsuda A;Fernandez AG;Finkelstein D;Campbell M;Kallappagoudar S;Jablonowski CM;Andrews AJ;Hiraoka Y;Partridge JF
对癌症基因组的测序已经在组蛋白中发现了反复出现的体细胞突变，称为癌组织蛋白，通常人们对此知之甚少。此前，我们发现在儿童侵袭性胶质瘤中只表达H3.3G34R突变体的裂解酵母减少了H3K36的三甲基化和乙酰化，增加了基因组的不稳定性和复制应激，以及缺陷的同源依赖的DNA损伤修复。在这里，我们发现G34V(也在胶质瘤中)和G34W(骨巨细胞瘤)突变导致了令人惊讶的不同表型，不同地影响H3K36修饰、亚端粒沉默、基因组稳定性；对辐射、烷化剂和羟基脲的敏感性；并影响DNA修复。在癌症中，编码H3的30个等位基因中只有1个发生突变。虽然野生型H3的共表达挽救了大多数G34突变表型，但G34R导致显性羟基尿素敏感性、同源重组缺陷和显性亚端粒沉默。总而言之，这些研究证明了与H3中的一个残基上的不同替换相关的复杂性，并强调了遗传易处理系统对其分析的实用性。
Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair. Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability; sensitivity to irradiation, alkylating agents, and hydroxyurea; and influencing DNA repair. In cancer, only 1 of 30 alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity, homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.