RNA biogenesis and genome homeostasis
Multiple DNA- and RNA-related transactions coexist in eukaryotic nuclei, their synchronization being critical for genome homeostasis. In this frame, mRNA metabolism has recently emerged as an unappreciated player, not only in the gene expression process, but also in the maintenance of genome stability (Fig. 1). On the one hand, the combinatorial association of RNA-binding proteins (RBPs) with mRNAs control their synthesis, processing, transport and turnover, ultimately defining their cellular fate and their translation into proteins. On the other hand, proper mRNA biogenesis counteracts the accumulation of R-loops: these structures, which comprise DNA:mRNA hybrids and displaced strands of DNA, can increase genome sensitivity to genotoxic agents and interfere with its replication, triggering transcription-associated genetic instability in a wide range of species. To keep in check mRNA biogenesis, the activities of several multiprotein machineries are thereby coupled along the mRNA production line, from transcription to nuclear export, and targeted by a number of quality control and regulatory mechanisms. Consistently, uncoupling the different steps of the mRNA biogenesis process has deleterious effects for both gene expression and genome stability, as exemplified in a number of physiological, mutant or pathological situations, including cancer (Fig. 1).
Our research activities aim to uncover cis- and trans-acting regulations of mRNA metabolism and to understand how they impact gene expression patterns and genomic integrity. We are particularly interested in deciphering how mRNA biogenesis and R-loop formation further influence genome dynamics in space and time, from short-term changes in nuclear organization to long-term genomic alterations. For this purpose, we combine genome- and proteome-wide approaches with mechanistic studies, using primarily budding yeast as a model system to understand these conserved processes (Fig. 2). Over the last years, our work has thereby revealed novel features of mRNA biogenesis, including:
(1) the control of RBP activity through post-translational modifications (e.g. SUMO) ;
(2) the existence of collective regulations for functionally related mRNAs ;
(3) an unexpected and conserved role for introns in preventing R-loop formation and transcription-associated genetic instability.
Rouviere JO, Bulfoni M, Tuck A, Cosson B, Devaux F & Palancade B. (2018)
A SUMO-dependent feedback loop senses and controls the biogenesis of nuclear pore subunits.
Nature communications 9(1):1665
See the highlight by the CNRS/INSB.
Bonnet A, Grosso AR, Elkaoutari A, Coleno E, Presle A, Sridhara SC, Janbon G, Géli V, de Almeida SF & Palancade B. (2017)
Introns protect eukaryotic genomes from transcription-associated genetic instability
Mol Cell 67(4):608-621.e6
See the highlights by Science and the CNRS/INSB.
This work was featured as “article of the year 2017” by the SFBBM (Société Française de Biochimie et de Biologie Moléculaire)
Babour A, Dos-Santos J , Shen Q, Murray S, Gay A, Challal D, Fasken M, Palancade B, Corbett A, Libri D, Mellor J and Dargemont C. (2016)
The chromatin remodeler ISW1 licenses nuclear mRNAs for export to the cytoplasm.
Bonnet A, Bretes H & Palancade B. (2015)
« Nuclear pores affect distinct stages of intron-containing gene expression »
Nucleic Acids Research 43(8):4249-61
Bretes H, Rouviere JO, Léger T, Oeffinger M, Devaux F, Doye V and Palancade B. (2014)
Sumoylation of the THO complex regulates the biogenesis of a subset of mRNPs
Nucleic Acids Research 42(8):5043-58