Cul4-Ddb1 ubiquitin ligases facilitate DNA replication-coupled sister chromatid cohesion through regulation of cohesin acetyltransferase Esco2
Cul4-Ddb1 ubiquitin ligases facilitate DNA replication-coupled sister chromatid cohesion through regulation of cohesin acetyltransferase Esco2
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Cul4-Ddb1 泛素连接酶通过调节粘连蛋白乙酰转移酶 Esco2 促进 DNA 复制偶联姐妹染色单体的粘连
DOI：
10.1371/journal.pgen.1007685
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发表时间：
2019-02-01
期刊：
影响因子：
4.5
通讯作者：
Lou, Huiqiang
中科院分区：
文献类型：
--
作者：
Sun, Haitao;Zhang, Jiaxin;Lou, Huiqiang
粘着蛋白乙酰转移酶Esco 1和Esco 2在建立姐妹染色单体粘着中起重要作用。Esco 1和Esco 2是如何以DNA复制偶联的方式被控制来实现这一点的，在高等真核生物中还不清楚。在这里，我们表明，Cul 4-RING连接酶（CRL 4）在人类细胞中的姐妹染色单体凝聚中发挥着关键作用。Cul 4A、Cul 4 B或Ddb 1亚基的缺失显著降低正常内聚效率。我们还表明，Mms 22 L，酵母Mms 22的脊椎动物直系同源物，是Ddb 1和Cul 4相关因子（DCAFs）参与的凝聚力。一些证据表明，CRL 4与Esco 2而不是Esco 1有选择性相互作用。CRL 4或Esco 2的缺失导致Smc 3乙酰化缺陷，这可以通过HDAC 8抑制来挽救。更重要的是，CRL 4和PCNA都是有效稳定染色质上Esco 2和催化Smc 3乙酰化的介质。综上所述，我们提出了一个进化上保守的机制，其中CRL 4和PCNA调节Esco 2依赖的姐妹染色单体凝聚力的建立。我们鉴定了人Mms 22 L作为Cul 4-Ddb 1 E3泛素连接酶的底物特异性衔接子。Cul 4A、Cul 4 B或Ddb 1亚基的下调通过与Esco 2乙酰转移酶的相互作用引起乙酰化Smc 3的减少，然后损害293 T细胞中的姐妹染色单体凝聚力。我们发现Cul 4-Ddb 1-Mms 22 L E3连接酶和Esco 2在Smc 3乙酰化和姐妹染色单体凝聚中具有功能互补。有趣的是，Cul 4-Ddb 1 E3泛素连接酶和PCNA都有助于Esco 2介导的Smc 3乙酰化。综上所述，我们证明了一个进化上保守的机制，其中Cul 4-Ddb 1 E3泛素连接酶和PCNA调节Esco 2依赖的姐妹染色单体凝聚力的建立。
Cohesin acetyltransferases Esco1 and Esco2 play a vital role in establishing sister chromatid cohesion. How Esco1 and Esco2 are controlled to achieve this in a DNA replication-coupled manner remains unclear in higher eukaryotes. Here we show that Cul4-RING ligases (CRL4s) play a critical role in sister chromatid cohesion in human cells. Depletion of Cul4A, Cul4B or Ddb1 subunits substantially reduces normal cohesion efficiency. We also show that Mms22L, a vertebrate ortholog of yeast Mms22, is one of Ddb1 and Cul4-associated factors (DCAFs) involved in cohesion. Several lines of evidence suggest a selective interaction of CRL4s with Esco2, but not Esco1. Depletion of either CRL4s or Esco2 causes a defect in Smc3 acetylation which can be rescued by HDAC8 inhibition. More importantly, both CRL4s and PCNA act as mediators for efficiently stabilizing Esco2 on chromatin and catalyzing Smc3 acetylation. Taken together, we propose an evolutionarily conserved mechanism in which CRL4s and PCNA regulate Esco2-dependent establishment of sister chromatid cohesion. Author summary We identified human Mms22L as a substrate specific adaptor of Cul4-Ddb1 E3 ubiquitin ligase. Downregulation of Cul4A, Cul4B or Ddb1 subunit causes reduction of acetylated Smc3, via interaction with Esco2 acetyltransferase, and then impairs sister chromatid cohesion in 293T cells. We found functional complementation between Cul4-Ddb1-Mms22L E3 ligase and Esco2 in Smc3 acetylation and sister chromatid cohesion. Interestingly, both Cul4-Ddb1 E3 ubiquitin ligase and PCNA contribute to Esco2 mediated Smc3 acetylation. To summarise, we demonstrated an evolutionarily conserved mechanism in which Cul4-Ddb1 E3 ubiquitin ligases and PCNA regulate Esco2-dependent establishment of sister chromatid cohesion.