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

Publication ,  Journal Article
Chen, J; Crutchley, J; Zhang, D; Owzar, K; Kastan, MB
Published in: Cancer Discov
July 2017

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.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

July 2017

Volume

7

Issue

7

Start / End Page

766 / 781

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Signal Transduction
  • Ribosomal Proteins
  • Radiation, Ionizing
  • RNA-Binding Proteins
  • RNA Precursors
  • Protein Serine-Threonine Kinases
  • Protein Binding
  • Phosphatidylinositol 3-Kinases
  • Humans
 

Citation

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MLA
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Chen, J., Crutchley, J., Zhang, D., Owzar, K., & Kastan, M. B. (2017). Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers. Cancer Discov, 7(7), 766–781. https://doi.org/10.1158/2159-8290.CD-16-0908
Chen, Jing, John Crutchley, Dadong Zhang, Kouros Owzar, and Michael B. Kastan. “Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.Cancer Discov 7, no. 7 (July 2017): 766–81. https://doi.org/10.1158/2159-8290.CD-16-0908.
Chen J, Crutchley J, Zhang D, Owzar K, Kastan MB. Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers. Cancer Discov. 2017 Jul;7(7):766–81.
Chen, Jing, et al. “Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.Cancer Discov, vol. 7, no. 7, July 2017, pp. 766–81. Pubmed, doi:10.1158/2159-8290.CD-16-0908.
Chen J, Crutchley J, Zhang D, Owzar K, Kastan MB. Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers. Cancer Discov. 2017 Jul;7(7):766–781.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

July 2017

Volume

7

Issue

7

Start / End Page

766 / 781

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Signal Transduction
  • Ribosomal Proteins
  • Radiation, Ionizing
  • RNA-Binding Proteins
  • RNA Precursors
  • Protein Serine-Threonine Kinases
  • Protein Binding
  • Phosphatidylinositol 3-Kinases
  • Humans