Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3′ untranslated regions (3′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3′ UTRs and reduced gene expression. Genes that harbor longer 3′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core “AGAA” motif located in the alternative 3′ UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.

细胞衰老已被认为是一种肿瘤抑制机制，也是个人衰老的一个原因。最近在癌细胞中发现了通过替代性聚腺苷酸化（APA）使信使RNA（mRNA）中3'非翻译区（3'UTR）广泛缩短的现象。但是，APA在细胞衰老过程中的作用仍然难以捉摸。在这里，我们发现衰老细胞中的数百个基因倾向于使用远侧的poly（A）（pA）位点，从而导致3'UTR的整体延长和基因表达的减少。在衰老细胞中具有更长3'UTR的基因富含衰老相关途径。Rras2，参与多个信号转导途径的Ras超家族成员，更喜欢使用更长的3'UTR并在衰老细胞中表现出降低的表达。Rras2的消耗促进衰老，而Rras2的抢救逆转了衰老相关的表型。机械上，剪接因子TRA2B与位于Rras2的备选3'UTR中的核心“ AGAA”基序结合，从而降低RRAS2蛋白水平并引起衰老。近端和远端poly（A）信号均显示出强大的序列保守性，突显了APA调控在进化过程中的重要作用。我们的研究结果揭示了APA是调节细胞衰老的新机制。