Cód. SSPA: IBiS-C-12
The gene expression laboratory is a multidisciplinary group that studies the molecular mechanisms of the expression and stability of eukaryotic genomes with utmost attention to their possible relationship with human disease. There are three main lines of work that encompass the regulation of gene expression, the control of the cell cycle and division, and the repair of DNA damage.
Research Lines
- Regulation of Gene Expression
Our group addresses gene expression regulation with an integrated vision to discover the relationships between higher levels of molecules, pathways and cellular structures that are required. Thus, one of our objectives is to elucidate the mechanisms controlling the cellular concentration of mRNA and rRNA (RNA ribostasis) in Saccharomyces cerevisiae and higher eukaryotes cell lines. We are also, specially interested in factors affecting RNA pol II transcription. We have characterized the functional role of canonical prefoldin in transcription elongation both in yeast and human cells and plays a role in co-transcriptional splicing in human cells. This transcriptional function of prefoldin seems to influence epithelium to mesenchyme transition in lung cancer. By this reason, the prefoldin studies have a strong translational potential.
Leading contact: Sebastián Chávez (schavez@us.es)
- Control of the Cell Cycle and Division
We are interested in processes in which a readjustment of different transcriptional parameters is needed to maintain ribostasis as: proliferation through the cell cycle, volume changes, aging and proliferative heterogeneity. S. cerevisiae seems to undergo proliferative heterogeneity from early divisions in a process involving Whi5 (the functional paralog of the Rb protein in mammalian cells) which is a negative regulator of the G1/S that controls the volume of the mother cell. The replicative age in S. cerevisiae is an integrating phenomenon of other aspects addressed in our group for the global study of ribostasis, such as cell volume, proliferation and the cell cycle. As the replicative age increase entails changes in the proliferation capacity, these must be mediated by changes in the regulation of the cell cycle that we try to elucidate.
Leading contact: MªCruz Muñoz Centeno (mmunoz@us.es)
- DNA Repair
Transcriptional stress is the consequence of either accidental or deliberate blockage of RNA polymerase progression and can result in the formation of DNA double strand breaks (DSBs), the most cytotoxic lesions occurring in the DNA. Gene expression is consequently one of the main endogenous sources of chromosome breakage. These breaks can promote cell death and genome instability, often associated with cancer. Notably, some of these breaks are the origin of recurrent chromosomal translocations, key events in the development of solid tumours and leukemias. However, how transcriptional activity can cause these breaks, and the cellular mechanisms of control and repair them remain unclear. Our group aims to elucidate the molecular mechanism of formation and repair of transcription-induced DNA breaks and their effect on genome integrity. In addition to the relevance from the genome stability perspective, understanding transcription associated DNA breaks presents the added value of well-established connections with human disease.
Leading contact: Fernando Gómez Herreros (fgomezhs@us.es)
- Assembly of multifunctional transcription complexes
Gene expression regulation is crucial for every organism to adapt to a fluctuating environment. A critical step in this process is transcription, which involves many different factors, frequently found as part of multifunctional protein complexes, such as SAGA, NuA4 or TFIID, among others. There has been extensive characterization of the individual subunits of these complexes and their regulation. However, much less is known about how, when and where these complexes are assembled. Defects in assembly are associated with multiple human diseases, including cancer. Aneuploid cancer cells express non-stoichiometric amounts of complex subunits, which favors the formation of uncomplete, non-functional complexes, as well as protein aggregation, generating proteotoxic stress. Cancer cells compensate this phenomenon by overexpressing chaperones and the proteasome, to maintain their proliferative capacity. Inhibitors of these cellular machineries are under investigation for cancer treatment. However, because of their global role in cell homeostasis, undesirable secondary effects are frequent, and more specific targets are needed. We aim to contribute to this topic by understanding the molecular rules and mechanisms controlling protein complex assembly, including the identification of assembly factors for specific complexes. This would allow to design more specific drug targets as to envision creating cancer-personalized treatments in the future. In the long term, our research should also set the basis for the in vitro reconstitution of protein complexes with desire activities, which has a strong biomedical potential.
Leading contact: Alberto Elías Villalobos (aelias1@us.es)
