The circadian Control of DNA end Resection

Even though double-strand breaks (DSBs) stand as the most cytotoxic lesion the cell can endure, they have evolved two major pathways to counter these: the religation of the broken ends (Non-Homologous End-Joining, NHEJ) and the repair of the lesion using a homologue sequence (Homology-Directed Repair, HDR). The choice between these two pathways is crucial for cell fitness and is controlled by an exquisite regulatory system. In this thesis, we uncovered a novel role for the circadian clock in the regulation of DNA end resection, the licensing step of HDR. Thus, we demonstrated that the circadian factor CRY1 drives circadian oscillations in DNA end resection, which results in circadian fluctuations in HDR. Mechanistically, we show how this protein is recruited to the DSB in a manner dependent on the apical kinase DNA-PK and favors the retention of the anti-resection factor CCAR2, which counteracts CtIP, the key factor permitting DNA end processing. Furthermore, not only do we describe how CRY1 expression levels impact genome stability and modulate cancer response to treatment, but also how time of the day impacts cancer response to radiation therapy as a reflection of this.

Author dc:creator

• Romero Franco, Amador

Advisor dc:contributor.advisor

• Huertas Sánchez, Pablo

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/11441/177460

OAI identifier oai:identifier

oai:idus.us.es:11441/177460