title: Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.
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 suppressorTP53, 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 humanTP53mRNA. 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.|Duke Cancer Institute, Duke University, Durham, North Carolina.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.|Duke Cancer Institute, Duke University, Durham, North Carolina.
authors.forename: John
authors.initials: J
authors.lastname: Crutchley
authors.affiliation: Duke Cancer Institute, Duke University, Durham, North Carolina.
authors.forename: Dadong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Duke Cancer Institute, Duke University, Durham, North Carolina.|Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina. michael.kastan@duke.edu.|Duke Cancer Institute, Duke University, Durham, North Carolina.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D017398:Alternative Splicing / Q000235:genetics / Q000528:radiation effects; D064113:CRISPR-Cas Systems / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics* / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases; D012322:RNA Precursors / Q000235:genetics / Q000528:radiation effects; D016601:RNA-Binding Proteins / Q000235:genetics; D011839:Radiation, Ionizing; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C489216:RPL26 protein, human; C495901:TP53 protein, human; C514704:SMG1 protein, human