Crosstalk between DNA end resection and RNA metabolism

DNA suffers thousands of lesions from exogenous and endogenous sources. Nevertheless, double-strand breaks (DSBs) are the most dangerous form of DNA damage because if they are not properly repaired they can lead to mutations and genomic instability. In order to repair them, cells have developed two major pathways: Homologous Recombination and Non-Homologous End-Joining. CtIP is a key protein in this response since it promotes faithful repair of DSBs by licensing homologous recombination. Recently, a crosstalk between DNA Damage Response (DDR) and RNA metabolism at different levels has been discovered. Thus, in this Thesis we studied this relationship deeply. We described that the splicing complex SF3B is involved in in DNA damage repair. Although part of such function is through CtIP, we observed that SF3B plays additional roles in DNA double strand break repair that are independent of its functional relationship with this factor. Additionally, we demonstrated that this relationship is bidirectional, since CtIP is involved in DNA damage-dependent and independent alternative mRNA splicing of several genes. The careful study of the CtIPdependent splicing of one of those genes, the one that codes the helicase PIF1, suggest that those events are important for the fine tuning of the DNA damage response. Furthermore, we reported a crosstalk between the DDR and RNA editing. RNA editing is, indeed, upregulated upon exposure to DNA damage in a fashion that requires CtIP and the checkpoint kinase ATR. Moreover, our data agree with the idea that the RNA editing enzymes ADARs have a role in the removal of DNA:RNA hybrids that facilitates DSB repair.

Author dc:creator

• Prados Carvajal, Rosario

Advisor dc:contributor.advisor

• Huertas Sánchez, Pablo

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 Internacional

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/11441/93475

OAI identifier oai:identifier

oai:idus.us.es:11441/93475