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Deubiquitinase USP47-stabilized splicing factor IK regulates the splicing of ATM pre-mRNA.
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-05-04 , DOI: 10.1038/s41420-020-0268-1
Hye In Ka 1 , Sunyi Lee 2 , Sora Han 3 , Ae Lee Jeong 4 , Ji Young Park 1 , Hyun Jeong Joo 1 , Su Jung Soh 1 , Doyeon Park 1 , Young Yang 1
Affiliation  

IK depletion leads to an aberrant mitotic entry because of chromosomal misalignment through the enhancement of Aurora B activity at the interphase. Here, we demonstrate that IK, a spliceosomal component, plays a crucial role in the proper splicing of the ATM pre-mRNA among other genes related with the DNA Damage Response (DDR). Intron 1 in the ATM pre-mRNA, having lengths <200 bp, was not spliced in the IK-depleted cells and led to a deficiency of the ATM protein. Subsequently, the IK depletion-induced ATM protein deficiency impaired the ability to repair the damaged DNA. Because the absence of SMU1 results in IK degradation, the mechanism underlying IK degradation was exploited. IK was ubiquitinated in the absence of SMU1 and then subjected to proteolysis through the 26S proteasome. To prevent the proteolytic degradation of IK, a deubiquitinating enzyme, USP47, directly interacted with IK and stabilized it through deubiquitination. Collectively, our results suggest that IK is required for proper splicing of the ATM pre-mRNA and USP47 contributes toward the stabilization of IK.

中文翻译:

去泛素酶 USP47 稳定的剪接因子 IK 调节 ATM 前 mRNA 的剪接。

由于间期 Aurora B 活性增强导致染色体错位,IK 耗尽会导致异常的有丝分裂进入。在这里,我们证明 IK(一种剪接体成分)在 ATM 前 mRNA 以及与 DNA 损伤反应 (DDR) 相关的其他基因的正确剪接中发挥着至关重要的作用。ATM 前体 mRNA 中的内含子 1 长度<200 bp,在 IK 耗尽的细胞中未剪接,导致 ATM 蛋白缺陷。随后,IK 耗竭引起的 ATM 蛋白缺陷损害了修复受损 DNA 的能力。由于 SMU1 的缺失会导致 IK 退化,因此我们利用了 IK 退化的潜在机制。IK 在没有 SMU1 的情况下被泛素化,然后通过 26S 蛋白酶体进行蛋白水解。为了防止 IK 被蛋白水解降解,去泛素化酶 USP47 直接与 IK 相互作用,并通过去泛素化使其稳定。总的来说,我们的结果表明 IK 是 ATM 前 mRNA 正确剪接所必需的,并且 USP47 有助于 IK 的稳定。
更新日期:2020-05-04
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