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

by Fernando Mej ías-Navarro, Guillermo Rodríguez-Real, Javier Ramón, Rosa Camarillo, Pablo Huertas 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 r esection 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 chrom atin 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 stab ilize the most abundant splicing form ofCtIP mRNA. This function relies on the presence of a specific RNA sequence in the 5 ′ UTR ofCtIP. Therefore, we describe an additional layer of regulation of CtIP —at the level of mRNA stability through ALC1 and eIF4A1.
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research