Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.
Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.
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DOI：
10.1158/2159-8290.cd-16-0908
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发表时间：
2017-07
期刊：
影响因子：
28.2
通讯作者：
Kastan MB
中科院分区：
文献类型：
--
作者：
Chen J;Crutchley J;Zhang D;Owzar K;Kastan MB
细胞对DNA损伤的反应是癌症发展和衰老相关发病机制的关键决定因素。在这里，我们报道了一种新的DNA损伤反应通路，它调节许多基因产物的选择性剪接，包括人类肿瘤抑制因子P53，并控制DNA损伤诱导的细胞衰老。总之，电离辐射抑制了磷脂酰肌醇-3-激酶样激酶(Pikk)家族成员HSMG-1的活性，减少了hSMG1与P53前体基因外显子9附近特定区域的结合，促进了核糖体蛋白L26(RPL26)与P53前基因的结合。RPL26反过来又是富含丝氨酸/精氨酸的剪接因子SRSF7招募到P53前β所必需的，并产生选择性剪接的P53 RNARNA。通过选择性地敲除P53β或下调途径成分来阻断这一途径，可以显著减少IR诱导的衰老标志物，并且缺乏P53β表达的细胞不能在转录上抑制细胞衰老和衰老的负调控。
Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here we report a novel DNA damage response pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor p53, and controls DNA damage-induced cellular senescence. In brief, ionizing irradiation (IR) inhibits the activity of hSMG-1, a phosphoinositide-3-kinase-like kinase (PIKK) family member, reducing the binding of hSMG1 to a specific region of p53 precursor mRNA near exon 9 and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA. RPL26, in turn, is required for the recruitment of the Serine/Arginine-rich splicing factor, SRSF7, to p53 pre-mRNA and generation of alternatively spliced p53β RNA. Disruption of this pathway via selective knockout of p53β by CRISPR/Cas9 or down-regulation of pathway constituents significantly reduces IR-induced senescence markers and cells lacking p53β expression fail to transcriptionally repress negative regulators of cellular senescence and aging.