Human Cryptochrome1 dampens homologous recombination at nightfall

Abstract

AbstractThe maintenance of genomic stability is essential for cellular and organismal survival and fitness. Thus, when DNA gets damaged, is essential to repair it in the most accurate fashion. Among different DNA lesions, DNA double strand breaks are specially challenging. An exquisite regulatory network reacts to local and global cues to control the choice between different DNA double strand break repair mechanisms to maximize genomic integrity. Such regulation relies mostly at the level of DNA end resection, the initial steps of the homologous recombination repair pathway. On the other hand, most cellular and organismal activities follow a 24 h oscillation known as the circadian cycle. Such repetitive changes are controlled by an intrinsic, molecular clock built-in at the cellular level which core components are the heterodimers BMAL1-CLOCK and CRY-PER. These inherent rhythms control many different aspects of the cellular metabolism, including the fate of many different DNA transactions. Here we have explored the regulation of the choice between different DNA double strand break repair pathways along the circadian cycle. We observed that DNA end resection shows a circadian oscillation, with a peak at dawn followed by a progressive reduction until dusk. Such regulations depend on the cellular levels of the circadian clock core component CRY1. Consequently, repair by homologous recombination mirrors CRY1 expression levels. Such modulation is controlled through the circadian regulation of the anti-resection activity, but not the protein levels, of CCAR2, that limits CtIP-mediated resection preferentially at nightfall. Additionally, such regulation requires a crosstalk between the DNA damage-dependent phosphorylation of CRY1 by the kinase DNA-PK. Finally, such regulation has an impact in cancer progression and response to radiation therapy of specific tumors.One sentence summaryCCAR2-dependent inhibition of DNA end resection and homologous recombination is controlled by the intrinsic cellular circadian clock