Identification of a DNA Damage–Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers
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Abstract
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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p53β is required for senescence induction, possibly through transcriptional repression.
“Functionally, p53β is required for senescence induction, possibly through transcriptional repression [202].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [202]
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Mechanisms and Regulation of Cellular Senescence
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- Authors
- Chen, J., Crutchley, J., Zhang, D., Owzar, K., & Kastan, M. B.
- Affiliations
- Duke University (US)
- Corresponding author
- Kastan, Michael B.
- Venue
- Cancer Discovery
- Published
- 2017-07-01
- Volume
- 7
- Issue
- 7
- Pages
- 766-781
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5501752
- OpenAlex
- W2595953303
- Cited by
- 93
- References
- 58
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 6 · 2023: 12 · 2022: 11 · 2021: 20 · 2020: 14 · 2019: 7 · 2018: 3 · 2017: 2
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01ES005777 and P30CA014236)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- DNA damage response, alternative splicing, p53, cellular senescence, SMG1, RPL26, SRSF7, ionizing radiation, pre-mRNA splicing, aging, tumor suppressor regulation
- MeSH terms
- DNA Damage, Humans, Protein Binding, Radiation, Ionizing, Ribosomal Proteins, RNA Precursors, Signal Transduction, Tumor Suppressor Protein p53, RNA-Binding Proteins, Cellular Senescence, Protein Serine-Threonine Kinases, Alternative Splicing, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, CRISPR-Cas Systems
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