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 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.This work was financed by an R+D+I grant from the Spanish Ministry of Economy and Competitivity (SAF2016-74855-P) and by the European Union Regional Funds (FEDER). FM-N was funded with an FPU fellowship from the Spanish Ministry of Education, and JR and GR-R were supported by the Regional Government of Andalucía (Junta de Andalucía) with a contract of the program “GARANTÍA JUVENIL EN LA UNIVERSIDAD DE SEVILLA”. CABIMER is supported by the regional government of Andalucía (Junta de Andalucía).Peer reviewe