Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.

Published

Journal Article

Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor TP53, and controls DNA damage-induced cellular senescence. In brief, ionizing radiation (IR) inhibits the activity of SMG1, a phosphoinositide-3-kinase-like kinase family member, reducing the binding of SMG1 to a specific region near exon 9 of p53 precursor mRNA 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 downregulation 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.Significance: We identified a new component of the DDR pathway that regulates alternative splicing of messenger RNAs, including human TP53 mRNA. Modulation of this regulatory pathway affects DNA-damage induction of cellular senescence markers. Cancer Discov; 7(7); 766-81. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.

Full Text

Duke Authors

Cited Authors

  • Chen, J; Crutchley, J; Zhang, D; Owzar, K; Kastan, MB

Published Date

  • July 2017

Published In

Volume / Issue

  • 7 / 7

Start / End Page

  • 766 - 781

PubMed ID

  • 28288992

Pubmed Central ID

  • 28288992

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-16-0908

Language

  • eng

Conference Location

  • United States