Projects
The Lopez-Aviles group will simultaneously run the following projects:
Identification of the mitotic phosphatase(s).
Using a combination of deletion mutants as well as conditional auxin-inducible degron (AID) alleles of the major phosphatases in fission yeast, we investigate how loss of phosphatase activity delays mitotic progression and affects the ordering of mitotic exit events.
Recent work from our laboratory has shown that, during a sustained mitotic arrest, loss of different phosphatases results in dramatically different outcomes. Importantly, the absence of PP2A-B55 results in premature cytokinesis in the presence of high CDK activity and unsegregated chromosomes. Nevertheless, we still lack information on the particular substrates of this phosphatase regulating mitotic events. Here, using proteomic approaches we aim at unveiling relevant targets of PP2A-B55 during mitotic exit.
Deciphering the roles of PP2A-B55 in chromatin regulation during proliferation and quiescence:
Cells of all organisms have the ability to withdraw from the cell cycle and become quiescent. This state is reversible and protects the cell from environmental insults. The study of quiescence is highly relevant to human disease: cancer cells that become quiescent are less sensitive to therapies and are thought to be the foundation for secondary tumors. In addition, for human pathogens, quiescence favors resistance to treatments.
One key aspect in the regulation of quiescence is the formation of a specific chromatin landscape. This is essential to bring about a transcriptional signature aimed at repressing cell proliferation and growth. In all organisms, TOR signaling promotes proliferation and prevents quiescence in response to nutrient availability. Nevertheless, how TOR conveys these signals to the machinery regulating chromatin status is unclear. Work in fission yeast from my laboratory showed that the phosphatase PP2A-B55 is a key mediator of TOR functions. Upon nutritional deprivation, inactivation of PP2A-B55 (mediated by the kinase Greatwall and its substrate ENSA) is required for the expression of the quiescence transcriptional program. We have initial evidence of the relation between PP2A-B55 chromatin remodelers and histone deacetylases, which posits PP2A-B55 as the link between TOR signaling and chromatin regulation. In this project we investigate the involvement of chromatin factors associated to PP2A- B55 in the establishment of quiescence, we aim at defining the chromatin landscape of quiescence and we study the molecular mechanisms behind.
Regulation of protein homeostasis in response to stress in fission yeast
The overarching question of the project revolts around understanding how protein homeostasis can be sustained in the face of environmental challenges, using as model organism the fission yeast Schizosaccharomyces pombe.
The project aims at investigating the interplay between signalling pathways activated in response to different stress conditions, the formation of stress granules and the machinery responsible for the quality controls associated to protein translation.