Biology subjects

Rodriguez-Real, G.

Publications and source records attributed to Rodriguez-Real, G..

3 recordsLinked to original sources

bioRxiv2022

Centriolar subdistal appendages promote double strand break repair through homologous recombination

The centrosome is a cytoplasmic organelle with roles in microtubule organization which has also been proposed to act as a hub for cellular signaling. Some centrosomal components are required for full activation of the DNA Damage Response. However, if the centrosome regulates specific DNA repair pathways is not known. Here, we show that centrosomes presence is required to fully activate recombination, specifically to completely license its initial step, the so-called DNA end resection. Furthermore, we identify a centriolar structure, the subdistal appendages, and a specific factor, CEP170, as the critical centrosomal component involved in the regulation of recombination and resection, albeit it does not control end-joining repair. Cells lacking centrosomes or depleted for CEP170 are, consequently, hyper-sensitive to DNA damaging agents. Moreover, low levels of CEP170 in multiple cancer types correlate with an increase of the mutation burden associated with specific mutational signatures and a better prognosis, suggesting that changes in CEP170 can act as a mutation driver but also could be targeted to improve current oncological treatments.

cell biology↗

bioRxiv2021

ADAR2-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair

The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the RNA Editing DAmage Response (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution. One sentence summaryDNA recombination requires RNA editing of DNA:RNA hybrids to ease their melting and facilitate DNA end resection

genetics↗

bioRxiv2019

CtIP -mediated alternative mRNA splicing finetunes the DNA damage response

In order to survive to the exposure of DNA damaging agents, cells activate a complex response that coordinates the cellular metabolism, cell cycle progression and DNA repair. Among many other events, recent evidence has described global changes in mRNA splicing in cells treated with genotoxic agents. Here, we explore further this DNA damage-dependent alternative splicing. Indeed, we show that both the splicing factor SF3B2 and the repair protein CtIP contribute to the global pattern of splicing both in cells treated or not to DNA damaging agents. Additionally, we focus on a specific DNA damage- and CtIP-dependent alternative splicing event of the helicase PIF1 and explore its relevance for the survival of cells upon exposure to ionizing radiation. Indeed, we described how the nuclear, active form of PIF1 is substituted by a splicing variant, named vPIF1, in a fashion that requires both the presence of DNA damage and CtIP. Interestingly, timely expression of vPIF1 is required for optimal survival to exposure to DNA damaging agents, but early expression of this isoform delays early events of the DNA damage response. On the contrary, expression of the full length PIF1 facilitates those early events, but increases the sensitivity to DNA damaging agents if the expression is maintained long-term.

molecular biology↗