Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth
Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth
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DOI：
10.1073/pnas.1511377112
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发表时间：
2015-11-17
影响因子：
11.1
通讯作者：
Lewis, Zachary A.
中科院分区：
文献类型：
--
作者：
Basenko, Evelina Y.;Sasaki, Takahiko;Lewis, Zachary A.
H3K9甲基化通过招募多个含异染色质蛋白1 （HP1）的复合物，使DNA中的组蛋白去乙酰化和胞嘧啶碱基甲基化，从而指导异染色质的形成。在粗神经孢子虫中，一个单一的H3K9甲基转移酶复合物，称为DIM-5，-7,-9, CUL4， DDB1复合物（DCDC），是正常生长发育所必需的。dcdc缺陷突变体对基因毒性物质甲基磺酸盐（MMS）敏感，但基因毒性胁迫的分子基础尚不清楚。我们发现dcdc缺陷菌株的MMS敏感性和生长表型都受到胚胎外胚层发育或Su-(var)3-9突变的抑制；E (z);Trithorax (set)-7编码H3K27甲基转移酶Polycomb抑制复合物-2 （PRC2）的组分。三甲基化组蛋白H3K27 （H3K27me3）在DCDC-或hpc -缺陷突变体中经历全基因组重分布到组成型异染色质，并且引入H3K27错义突变足以挽救DCDC-缺陷菌株的表型。H3K27me3在异染色质中的积累不能弥补沉默；相反，缺乏DCDC和PRC2的菌株对拓扑异构酶I抑制剂喜树碱表现出合成敏感性，并在异染色质上积累伽马H2A。总之，这些数据表明PRC2调节对基因毒性应激的反应。
H3K9 methylation directs heterochromatin formation by recruiting multiple heterochromatin protein 1 (HP1)-containing complexes that deacetylate histones and methylate cytosine bases in DNA. In Neurospora crassa, a single H3K9 methyltransferase complex, called the DIM-5,-7,-9, CUL4, DDB1 Complex (DCDC), is required for normal growth and development. DCDC-deficient mutants are hypersensitive to the genotoxic agent methyl methanesulfonate (MMS), but the molecular basis of genotoxic stress is unclear. We found that both the MMS sensitivity and growth phenotypes of DCDC-deficient strains are suppressed by mutation of embryonic ectoderm development or Su-(var)3-9; E(z); Trithorax (set)-7, encoding components of the H3K27 methyltransferase Polycomb repressive complex-2 (PRC2). Trimethylated histone H3K27 (H3K27me3) undergoes genome-wide redistribution to constitutive heterochromatin in DCDC- or HP1-deficient mutants, and introduction of an H3K27 missense mutation is sufficient to rescue phenotypes of DCDC-deficient strains. Accumulation of H3K27me3 in heterochromatin does not compensate for silencing; rather, strains deficient for both DCDC and PRC2 exhibit synthetic sensitivity to the topoisomerase I inhibitor Camptothecin and accumulate gamma H2A at heterochromatin. Together, these data suggest that PRC2 modulates the response to genotoxic stress.