Alternative polyadenylation dependent function of splicing factor SRSF3 contributes to cellular senescence
Alternative polyadenylation dependent function of splicing factor SRSF3 contributes to cellular senescence
复制标题
剪接因子 SRSF3 的替代多腺苷酸化依赖性功能导致细胞衰老
DOI：
10.18632/aging.101836
复制
发表时间：
2019-03-15
期刊：
影响因子：
5.2
通讯作者：
Ni, Ting
中科院分区：
文献类型：
--
作者：
Shen, Ting;Li, Huan;Ni, Ting
已知下调的剪接因子SRSF 3通过其在人类细胞中的选择性剪接依赖性功能促进细胞衰老，这是预防癌症和促进个体衰老的重要生物学过程。在这里，我们发现了替代的多聚腺苷酸化（阿帕）依赖功能的SRSF 3作为一种新的机制，解释SRSF 3下调诱导细胞衰老。SRSF 3基因敲除导致mRNA的3′非翻译区（3′ UTR）的整体缩短。SRSF 3-耗竭还在人和小鼠细胞中诱导衰老相关表型。这些3′ UTR缩短的基因在衰老相关通路中富集。缩短的3′ UTR比长的3′ UTR产生更多的蛋白质。通过过表达三个候选基因（PTEN、PIAS 1和DNMT 3A）来模拟3′ UTR缩短的效应，均导致衰老相关表型。在3′ UTR缩短基因中，SRSF 3在近端poly（A）位点的结合密度高于远端poly（A）位点。此外，通过异位过表达或SRSF 3敲低诱导的PTEN上调均导致AKT磷酸化减少，并最终导致衰老相关表型。我们首次揭示了减少SRSF 3表达可以通过其APA依赖性功能促进细胞衰老，这在很大程度上扩展了我们对剪接因子调节细胞衰老的机制理解。
Down-regulated splicing factor SRSF3 is known to promote cellular senescence, an important biological process in preventing cancer and contributing to individual aging, via its alternative splicing dependent function in human cells. Here we discovered alternative polyadenylation (APA) dependent function of SRSF3 as a novel mechanism explaining SRSF3 downregulation induced cellular senescence. Knockdown of SRSF3 resulted in preference usage of proximal poly(A) sites and thus global shortening of 3′ untranslated regions (3′ UTRs) of mRNAs. SRSF3-depletion also induced senescence-related phenotypes in both human and mouse cells. These 3′ UTR shortened genes were enriched in senescence-associated pathways. Shortened 3′ UTRs tended to produce more proteins than the longer ones. Simulating the effects of 3′ UTR shortening by overexpression of three candidate genes (PTEN, PIAS1 and DNMT3A) all led to senescence-associated phenotypes. Mechanistically, SRSF3 has higher binding density near proximal poly(A) site than distal one in 3′ UTR shortened genes. Further, upregulation of PTEN by either ectopic overexpression or SRSF3-knockdown induction both led to reduced phosphorylation of AKT and ultimately senescence-associated phenotypes. We revealed for the first time that reduced SRSF3 expression could promote cellular senescence through its APA-dependent function, largely extending our mechanistic understanding in splicing factor regulated cellular senescence.