Abstract
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.
Highlights
In order to maintain genomic integrity, cells have to successfully deal with thousands of threats on a daily basis that could potentially compromise the structure or sequence of DNA [1]
The DNA molecule is constantly threatened by the appearance of physical or chemical modifications that endanger the integrity of the genetic information
CtIP is a key protein of pivotal importance in the decision between different broken DNA repair pathways
Summary
In order to maintain genomic integrity, cells have to successfully deal with thousands of threats on a daily basis that could potentially compromise the structure or sequence of DNA [1]. The appearance of one or more DSBs triggers a very complex response that is required to minimize genomic instability. This includes the activation of specific DSB repair pathways as well as of a cellular response that will affect virtually every aspect of metabolism, from cell cycle progression, to gene and protein expression [1]. HR is considered the most errorfree way to deal with a broken chromosome, at least when the sister chromatid is present [3]
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