SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes
SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes
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SIRT7 使 DDB1 去乙酰化并抑制 CRL4 E3 连接酶复合物的活性
DOI：
10.1111/febs.14264
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发表时间：
2017-11-01
期刊：
影响因子：
5.4
通讯作者：
Yuan, Hai-Xin
中科院分区：
文献类型：
--
作者：
Mo, Yan;Lin, Ran;Yuan, Hai-Xin
Cullin 4（CUL 4）和小无名指蛋白ROC 1组装形成E3遍在蛋白连接酶（CRL 4）复合物。CUL 4通过接头蛋白DNA损伤结合蛋白1（DDB 1）与WD-40蛋白相互作用以靶向底物进行泛素化。关于CUL 4和DDB 1相互作用是如何调节的知之甚少。在这里，我们表明，DDB 1是乙酰化和乙酰化促进DDB 1结合CUL 4。我们还确定核仁sirtuin 7（SIRT 7）作为一个主要的脱乙酰酶，负调控DDB 1-CUL 4相互作用。在通过放线菌素D或5-氟尿嘧啶处理或敲低RNA聚合酶I组分UBF的基因抑制核仁功能后，SIRT 7从核仁移动到核质并促进DDB 1脱乙酰化，导致DDB 1-CUL 4缔合和CRL 4活性降低。这导致包括LATS 1和p73在内的CRL 4底物的积累或活化，这有助于放线菌素D和5-氟尿嘧啶诱导的细胞凋亡。我们的研究揭示了一种新的调节CRL 4 E3连接酶复合物。
Cullin 4 (CUL4) and small ring finger protein ROC1 assemble to form E3 ubiquitin ligase (CRL4) complexes. CUL4 interacts with WD-40 proteins through the adaptor protein DNA damage-binding protein 1 (DDB1) to target substrates for ubiquitylation. Very little is known on how the CUL4 and DDB1 interaction is regulated. Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction. Following inhibition of nucleolar function by actinomycin D or 5-fluorouracil treatment or knocking down the gene for the RNA polymerase I component UBF, SIRT7 is mobilized from the nucleolus to the nucleoplasm and promotes DDB1 deacetylation, leading to decreased DDB1-CUL4 association and CRL4 activity. This results in the accumulation or activation of CRL4 substrates including LATS1 and p73, which contribute to cell apoptosis induced by actinomycin D and 5-fluorouracil. Our study uncovers a novel regulation of CRL4 E3 ligase complexes.