Integrator subunit 4 is a 'Symplekin-like' scaffold that associates with INTS9/11 to form the Integrator cleavage module.
Integrator subunit 4 is a 'Symplekin-like' scaffold that associates with INTS9/11 to form the Integrator cleavage module.
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DOI：
10.1093/nar/gky100
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发表时间：
2018-05-04
影响因子：
14.9
通讯作者：
Wagner EJ
中科院分区：
文献类型：
--
作者：
Albrecht TR;Shevtsov SP;Wu Y;Mascibroda LG;Peart NJ;Huang KL;Sawyer IA;Tong L;Dundr M;Wagner EJ
整合子（INT）是与RNA聚合酶II相关的转录调节复合物，其为UsnRNA和增强子RNA的3′-末端加工所需。整合子亚基9（INTS 9）和INTS 11构成INT的催化核心，并且是切割和聚腺苷酸化特异性因子CPSF 100和CPSF 73的旁系同源物。虽然已知CPSF 73/100与称为Symplekin的第三种蛋白质相关，但INT中没有Symplekin的蛋白质，这引发了INTS 9/11如何与其他INT亚基相关的问题。在这里，我们已经确定，INTS 4是一个特定的和保守的相互作用伙伴的INTS 9/11，不相互作用的任何一个亚基单独。虽然INTS 4与Symplekin没有显著的同源性，但它具有与Symplekin相似的N-末端HEAT重复序列，而且还含有富含β折叠的C-末端区域，这两者对于结合INTS 9/11都很重要。我们评估了INT的三种功能，包括UsnRNA 3′-末端加工，Cajal体结构完整性的维持和组蛋白位点体的形成，得出结论，INT 4/9/11是对UsnRNA生物发生最关键的INT亚基。总之，这些结果表明，INTS 4/9/11组成异源三聚体复合物，其可能代表负责其核酸内切活性的整合子“切割模块”。
Integrator (INT) is a transcriptional regulatory complex associated with RNA polymerase II that is required for the 3′-end processing of both UsnRNAs and enhancer RNAs. Integrator subunits 9 (INTS9) and INTS11 constitute the catalytic core of INT and are paralogues of the cleavage and polyadenylation specificity factors CPSF100 and CPSF73. While CPSF73/100 are known to associate with a third protein called Symplekin, there is no paralog of Symplekin within INT raising the question of how INTS9/11 associate with the other INT subunits. Here, we have identified that INTS4 is a specific and conserved interaction partner of INTS9/11 that does not interact with either subunit individually. Although INTS4 has no significant homology with Symplekin, it possesses N-terminal HEAT repeats similar to Symplekin but also contains a β-sheet rich C-terminal region, both of which are important to bind INTS9/11. We assess three functions of INT including UsnRNA 3′-end processing, maintenance of Cajal body structural integrity, and formation of histone locus bodies to conclude that INTS4/9/11 are the most critical of the INT subunits for UsnRNA biogenesis. Altogether, these results indicate that INTS4/9/11 compose a heterotrimeric complex that likely represents the Integrator ‘cleavage module’ responsible for its endonucleolytic activity.
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