PDF(Pubmed)
Abstract：
Canonical oncohistones are histone H3 mutations in the N-terminal tail associated with tumors and affect gene expression by altering H3 post-translational modifications (PTMs) and the epigenetic landscape. Noncanonical oncohistone mutations occur in both tails and globular domains of all four core histones and alter gene expression by perturbing chromatin remodeling. However, the effects and mechanisms of noncanonical oncohistones remain largely unknown. Here we characterized 16 noncanonical H2B oncohistones in the fission yeast Schizosaccharomyces pombe. We found that seven of them exhibited temperature sensitivities and 11 exhibited genotoxic sensitivities. A detailed study of two of these onco-mutants H2BG52D and H2BP102L revealed that they were defective in homologous recombination (HR) repair with compromised histone eviction and Rad51 recruitment. Interestingly, their genotoxic sensitivities and HR defects were rescued by the inactivation of the H2BK119 deubiquitination function of Ubp8 in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex. The levels of H2BK119 monoubiquitination (H2Bub) in the H2BG52D and H2BP102L mutants are reduced in global genome and at local DNA break sites presumably due to enhanced recruitment of Ubp8 onto nucleosomes and are recovered upon loss of H2B deubiquitination function of the SAGA complex. Moreover, H2BG52D and H2BP102L heterozygotes exhibit genotoxic sensitivities and reduced H2Bub in cis. We therefore conclude that H2BG52D and H2BP102L oncohistones affect HR repair and genome stability via the reduction of H2Bub and propose that other noncanonical oncohistones may also affect histone PTMs to cause diseases.
摘要：
典型的致癌组蛋白是与肿瘤相关的N末端尾部的组蛋白H3突变，并通过改变H3翻译后修饰（PTM）和表观遗传景观来影响基因表达。所有4种核心组蛋白的尾部和球形结构域均发生非规范的癌组蛋白突变，并通过干扰染色质重塑来改变基因表达。然而,非经典致癌组蛋白的作用和机制在很大程度上仍然未知。在这里，我们对裂殖酵母裂殖酵母中的16种非经典H2B致癌组蛋白进行了表征。我们发现其中7种表现出温度敏感性，11种表现出遗传毒性敏感性。对这些onco突变体H2BG52D和H2BP102L中的2种进行的详细研究表明，它们在同源重组（HR）修复中存在缺陷，组蛋白驱逐和Rad51募集受损。有趣的是,它们的基因毒性敏感性和HR缺陷通过在Spt-Ada-Gcn5-乙酰转移酶(SAGA)复合物中的Ubp8的H2BK119去泛素化功能失活而得以挽救.H2BG52D和H2BP102L突变体中的H2BK119单单泛素化（H2Bub）水平在全局和局部DNA断裂位点中降低，大概是由于Ubp8在核小体上的募集增强，并在SAGA复合物的H2B去泛素化功能丧失后恢复。此外，H2BG52D和H2BP102L杂合子表现出遗传毒性敏感性，并在顺式中减少H2Bub。因此，我们得出结论，H2BG52D和H2BP102L致癌组蛋白通过减少H2Bub影响HR修复和基因组稳定性，并提出其他非规范致癌组蛋白也可能影响组蛋白PTM引起疾病。
