Olga Calvo

Transcription Regulation

Regulation of gene expression is the result of the combined control of transcription and RNA processing in the nucleus, as well as translation and mRNA decay in the cytoplasm. One of these processes, transcription of protein-encoding genes by RNA polymerase II (RNAPII), plays a central role in gene expression in all living organisms. RNAPII transcription is highly regulated at many steps, including initiation, elongation and termination, and tightly coordinated and linked to many other nuclear functions in a complex web of connections. The central coordinator that directs this regulatory network is the RNAPII itself, being the carboxy-terminal domain (CTD) of its largest subunit of remarkable importance. Thus, RNAPII-CTD phosphorylation regulates and coordinates the entire transcription cycle with pre-mRNA processing and mRNA transport, and with chromatin remodeling and histone modifications. Therefore, RNAPII phosphorylation is one of the key processes in the regulation of gene expression in general. Consequently, deciphering the mechanisms that underlie RNAPII phosphorylation regulation has become one of the most studied issues in the field of gene expression.

The main goal of our research is to decipher the molecular mechanisms underlying transcription regulation, in general, and RNAPII phosphorylation. We have shown that Sub1, a transcriptional co-activator that play a role during transcription initiation, it is also implicated in other steps of mRNA metabolism. Thus, it influences RNAP II-CTD phosphorylation during the whole transcription cycle; and it associates with Spt5/4 elongation complex to influence transcription elongation rate. Sub1 has been implicated in several steps of mRNA metabolism in yeast, though the exact mechanism remains mostly unknown. More recently, we have shown that Rpb4 and Rpb7 subunits of eukaryotic RNAPII play a key role in controlling CTD phosphorylation (Allepuz-Fuster, 2014). Our data suggest a model in which Rpb4/7 helps recruit CTD-modifying enzymes (i.e. phosphatases), a role that is central to RNAPII function. We have recently shown that Sub1 interacts with the RNAPII via Rpb4/7 (Garavís et al, 2016). We are currently investigating the mechanism by which Sub1 and Rpb4/7 and its associated factors regulate and coordinate all these gene expression steps, and in particular CTD phosphorylation. For that purpose, we use as a model organism Saccharomyces cerevisiae, and several genetics, biochemistry and molecular biology techniques.

Hypothetical model showing that Sub1 associates with the chromatin during the whole transcription cycle, from preinitiation to termination, and is involved in several aspects of mRNA biogenesis, through the interaction with transcription initiation factors (TFIIB), elongation factors (Spt5) and termination-polyadenylation factors (PAFs). The Rpb4/7 heterodimer (4, 7) is a stalk-like protrusion extending from the main body of the RNAPII complex. Rpb4/7 is located near the RNA exit chanel and the CTD, thus agreeing with a role in the recruitment of factors for RNA biogenesis and /or CTD modification. Sub1 interacts with the DNA and the RNAPII via Rpb4/7 to modulate mRNA synthesis.

Group members
O. Calvo. (2017)
Sub1 and RNAPII, until termination does them part.
Transcription. In Press.
M. Garavís and O Calvo. (2017)
Sub1/PC4, a multifaceted factor:from transcription to genome stability.
Current Genetics. In Press.
Torreira E, Louro JL, Pazos I, González-Polo N , Gil-Carton D, Garcia-Duran A, Tosi S, Gallego O*, Calvo O*, Fernández-Tornero, C*. (2017)
The dynamic assembly of distinct RNA polymerase I complexes modulates rDNA transcription
DOI: http://dx.doi.org/10.7554/eLife.20832
Garavís M, González-Polo N, Allepuz-Fuster P, Louro JA, Fernández-Tornero C, Calvo O. (2017)
Sub1 contacts the RNA polymerase II stalk to modulate mRNA synthesis.
Nucleic Acids Research 45: 2458-2471.
Allepuz-Fuster P, Martínez-Fernández, V, Garrido-Godino AI, Alonso-Aguado S, Hanes SD, Navarro F and Calvo O. (2014)
Rpb4/7 facilitates RNA polymerase II CTD dephosphorylation.
Nucleic Acids Research 42: 13674-13688.
DOI: 10.1093/nar/gku1227
García A, Collin A and Calvo O (2012)
Sub1 associates with Spt5 and influences RNA polymerase II transcription elongation rate
Mol. Biol. Cell. 23: 4297-312
García A, Rosonina E, Manley JL, Calvo O. (2010)
Sub1 globally regulates RNA polymerase II CTD phosphorylation.
Molecular and Cellular Biology 30 - 21, pp. 5180 - 5193.
Research grants
MINECO: BFU2013-48374-P
Links of interest