Article ; Online: Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.
2023 Volume 199, Issue 4, Page(s) 406–421
Abstract: Altered cellular responses to DNA damage can contribute to cancer development, progression, and therapeutic resistance. Mutations in key DNA damage response factors occur across many cancer types, and the DNA damage-responsive gene, TP53, is frequently ... ...
Abstract | Altered cellular responses to DNA damage can contribute to cancer development, progression, and therapeutic resistance. Mutations in key DNA damage response factors occur across many cancer types, and the DNA damage-responsive gene, TP53, is frequently mutated in a high percentage of cancers. We recently reported that an alternative splicing pathway induced by DNA damage regulates alternative splicing of TP53 RNA and further modulates cellular stress responses. Through damage-induced inhibition of the SMG1 kinase, TP53 pre-mRNA is alternatively spliced to generate TP53b mRNA and p53b protein is required for optimal induction of cellular senescence after ionizing radiation-induced DNA damage. Herein, we confirmed and extended these observations by demonstrating that the ATM protein kinase is required for repression of SMG1 kinase activity after ionizing radiation. We found that the RNA helicase and splicing factor, DDX5, interacts with SMG1, is required for alternative splicing of TP53 pre-mRNA to TP53b and TP53c mRNAs after DNA damage, and contributes to radiation-induced cellular senescence. Interestingly, the role of SMG1 in alternative splicing of p53 appears to be distinguishable from its role in regulating nonsense-mediated RNA decay. Thus, ATM, SMG1, and DDX5 participate in a DNA damage-induced alternative splicing pathway that regulates TP53 splicing and modulates radiation-induced cellular senescence. |
---|---|
MeSH term(s) | Humans ; Alternative Splicing ; Protein Serine-Threonine Kinases/genetics ; RNA Precursors/genetics ; RNA Precursors/metabolism ; DNA Damage ; Neoplasms ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Ataxia Telangiectasia Mutated Proteins/metabolism |
Chemical Substances | Protein Serine-Threonine Kinases (EC 2.7.11.1) ; RNA Precursors ; Ddx5 protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; SMG1 protein, human (EC 2.7.11.1) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) |
Language | English |
Publishing date | 2023-03-11 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 80322-4 |
ISSN | 1938-5404 ; 0033-7587 |
ISSN (online) | 1938-5404 |
ISSN | 0033-7587 |
DOI | 10.1667/RADE-22-00219.1 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Ue I Zs.275: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.