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Mutual Balance of Histone Deacetylases 1 and 2 and the Acetyl Reader ATAD2 Regulates the Level of Acetylation of Histone H4 on Nascent Chromatin of Human Cells.
Molecular and Cellular Biology ( IF 5.3 ) Pub Date : 2020-04-13 , DOI: 10.1128/mcb.00421-19
Pavlo Lazarchuk 1 , John Hernandez-Villanueva 1 , Maria N Pavlova 1 , Alexander Federation 2 , Michael MacCoss 3 , Julia M Sidorova 4
Affiliation  

Newly synthesized histone H4 that is incorporated into chromatin during DNA replication is acetylated on lysines 5 and 12. Histone deacetylase 1 (HDAC1) and HDAC2 are responsible for reducing H4 acetylation as chromatin matures. Using CRISPR-Cas9-generated hdac1- or hdac2-null fibroblasts, we determined that HDAC1 and HDAC2 do not fully compensate for each other in removing de novo acetyls on H4 in vivo Proteomics of nascent chromatin and proximity ligation assays with newly replicated DNA revealed the binding of ATAD2, a bromodomain-containing posttranslational modification (PTM) reader that recognizes acetylated H4. ATAD2 is a transcription facilitator overexpressed in several cancers and in the simian virus 40 (SV40)-transformed human fibroblast model cell line used in this study. The recruitment of ATAD2 to nascent chromatin was increased in hdac2 cells over the wild type, and ATAD2 depletion reduced the levels of nascent chromatin-associated, acetylated H4 in wild-type and hdac2 cells. We propose that overexpressed ATAD2 shifts the balance of H4 acetylation by protecting this mark from removal and that HDAC2 but not HDAC1 can effectively compete with ATAD2 for the target acetyls. ATAD2 depletion also reduced global RNA synthesis and nascent DNA-associated RNA. A moderate dependence on ATAD2 for replication fork progression was noted only for hdac2 cells overexpressing the protein.

中文翻译:

组蛋白脱乙酰基酶1和2与乙酰基读取器ATAD2的相互平衡调节了组蛋白H4在人细胞新生染色质上的乙酰化水平。

在DNA复制过程中整合到染色质中的新合成的组蛋白H4在赖氨酸5和12上被乙酰化。组蛋白脱乙酰基酶1(HDAC1)和HDAC2负责在染色质成熟时减少H4乙酰化。使用CRISPR-Cas9生成的hdac1或hdac2无效的成纤维细胞,我们确定HDAC1和HDAC2在去除H4上的新生乙酰时,不能完全补偿彼此ATAD2的结合,ATAD2是一种识别溴化H4的含溴结构域的翻译后修饰(PTM)阅读器。ATAD2是在本研究中使用的几种癌症和猿猴病毒40(SV40)转化的人类成纤维细胞模型细胞系中过表达的转录促进因子。在hdac2细胞中,与野生型相比,ATAD2向新生染色质的募集增加,而ATAD2的消耗减少了野生型和hdac2细胞中新生染色质相关的乙酰化H4的水平。我们建议过表达的ATAD2通过保护该标记免于转移来转移H4乙酰化的平衡,并且HDAC2但不能HDAC1可以与ATAD2有效竞争目标乙酰基。ATAD2的消耗也减少了整体RNA的合成和与DNA相关的新生RNA。仅在过表达该蛋白的hdac2细胞中发现了对ATAD2复制叉进展的中等依赖性。我们建议过表达的ATAD2通过保护该标记免于转移来转移H4乙酰化的平衡,并且HDAC2但不能HDAC1可以与ATAD2有效竞争目标乙酰基。ATAD2的消耗也减少了整体RNA的合成和与DNA相关的新生RNA。仅在过表达该蛋白的hdac2细胞中发现了对ATAD2复制叉进展的中等依赖性。我们建议过表达的ATAD2通过保护该标记免于转移来转移H4乙酰化的平衡,并且HDAC2但不能HDAC1可以与ATAD2有效竞争目标乙酰基。ATAD2的消耗也减少了整体RNA的合成和与DNA相关的新生RNA。仅在过表达该蛋白的hdac2细胞中发现了对ATAD2复制叉进展的中等依赖性。
更新日期:2020-02-03
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