ALC1/eIF4A1-mediated regulation of CtIP mRNA stability controls DNA end resection

During repair of DNA double-strand breaks, resection of DNA ends influences how these lesions will be repaired. If resection is activated, the break will be channeled through homologous recombination; if not, it will be simply ligated using the non-homologous end-joining machinery. Regulation of res...

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Published inPLoS genetics Vol. 16; no. 5; p. e1008787
Main Authors Mejías-Navarro, Fernando, Rodríguez-Real, Guillermo, Ramón, Javier, Camarillo, Rosa, Huertas, Pablo
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 11.05.2020
Public Library of Science (PLoS)
Subjects
5' Untranslated Regions
Biology and life sciences
Cell adhesion & migration
Cell cycle
Chromatin
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Genetic research
Green fluorescent protein
Infrared imaging systems
Medicine and Health Sciences
Messenger RNA
Metabolism
mRNA stability
Plasmids
Post-translation
Proteins
Regulatory sequences
Research and Analysis Methods
Structure
Transcription factors
Spain
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Summary:During repair of DNA double-strand breaks, resection of DNA ends influences how these lesions will be repaired. If resection is activated, the break will be channeled through homologous recombination; if not, it will be simply ligated using the non-homologous end-joining machinery. Regulation of resection relies greatly on modulating CtIP, which can be done by modifying: i) its interaction partners, ii) its post-translational modifications, or iii) its cellular levels, by regulating transcription, splicing and/or protein stability/degradation. Here, we have analyzed the role of ALC1, a chromatin remodeler previously described as an integral part of the DNA damage response, in resection. Strikingly, we found that ALC1 affects resection independently of chromatin remodeling activity or its ability to bind damaged chromatin. In fact, it cooperates with the RNA-helicase eIF4A1 to help stabilize the most abundant splicing form of CtIP mRNA. This function relies on the presence of a specific RNA sequence in the 5' UTR of CtIP. Therefore, we describe an additional layer of regulation of CtIP-at the level of mRNA stability through ALC1 and eIF4A1.
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Current address: Mitochondrial Disorders Unit, Vall d’Hebron Institut de Recerca, Barcelona, Catalonia, Spain
The authors have declared that no competing interests exist.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1008787