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 p53 RNA. Disruption of this pathway via selective knockout of p53 by CRISPR/Cas9 or down-regulation of pathway constituents significantly reduces IR-induced senescence markers and cells lacking p53 expression fail to transcriptionally repress negative regulators of cellular senescence and aging.
- Received August 15, 2016.
- Revision received March 9, 2017.
- Accepted March 9, 2017.
- Copyright ©2017, American Association for Cancer Research.