María Moriel-CarreteroCentre de recherche en biologie cellulaire de Montpellier (CRBM) - CNRS / Université de Montpellier
I have devoted my career to better understand how the integrity of the genome is preserved, and how the cell copes with the situation when this process is not successful. In this way, during my PhD in the University of Sevilla, Spain, under the supervision of Dr. Andrés Aguilera, I uncovered an unprecedented crosstalk between two DNA repair pathways, namely Nucleotide Excision Repair and Homologous Recombination. I then moved to Montpellier, France, to the lab of Dr. Angelos Constantinou at the Institute of Human Genetics. I found that the Fanconi Anemia proteins FANCI and FANCD2, which normally are thought to work in DNA Repair only, had a basal role in the handling of splicing factors, a task that directly impacts transcription. I then worked in the same institute with Dr. Philippe Pasero, concentrating on yet another aspect of genome stability preservation: the replication process. In this second post-doctoral period, I demonstrated a novel role for a DNA damage signaling factor when replication forks were arrested. With this expertise in hand, I next wanted to explore another layer of complexity, being inspired by very recent evidence showing that caloric restriction leads to increased genome integrity: I aim at understanding how all these genome-preserving activities are influenced by the cytoplasmic context where the nucleus is embedded. At present, my team studies at the mechanistic detail a novel process by which the metabolism of lipids controls DNA damage sensing and repair.
Mon projet ATIP-Avenir
The Endoplasmic Reticulum impacts genome stability by buffering the DNA damage response
Genome integrity must be preserved to warrant cell fitness. Surveillance and repair occur within the cell nucleus to preserve the stability of the genome. Yet, the nucleus is not isolated: its timely interaction with the surrounding cytoplasm may impact how this task is achieved. Recent findings indicate that DNA repair by-products generated in the nucleus can induce an inflammatory response in the cytoplasm, giving us an example of the of the functional connection between these two compartments. My preliminary data indicate that DNA damage engenders stress in the Endoplasmic Reticulum (ER), a response that is needed to tolerate such damage. This project postulates that the nucleus and the ER conform a connected-vessels system whose continuity is essential for genome stability maintenance. The main goals are: 1) understanding how this link is established/regulated at the molecular level, 2) characterizing the precise events set into play after ER stress to allow DNA damage tolerance and 3) learning how to modulate this system for therapy purposes in both degenerative diseases and cancer. These goals will be achieved using Molecular Biology, Biochemistry and Genetics tools and trans-disciplinary strategies (Saccharomyces cerevisiae, Drosophila and different types of human cell lines, among which multiple myeloma).