Transcribing RNA polymerase

Benoit Coulombe, PhD

Director, Department of Translational Proteomics, IRCM

Bell-Bombardier Research Chair, IRCM

Professor, Department of Biochemistry & Molecular Medicine, U of Montréal

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Life Is Rooted in a Vast Dynamic Web of Protein-Protein Interactions

 

OVERVIEW

Our goal is to develop and apply high-specificity, high-sensitivity methods for mapping human protein-protein interactions (the interactome) and for characterizing interactome changes in various genetic and viral diseases. This knowledge accelerates biomarker and drug discovery en route to the development of more efficient diagnostics and therapeutics for various diseases.

Our group adopts a resolutely innovative modus operandi, which contributes to shaking up our classic methods by creating a transdisciplinary and open ecosystem where totally distinct approaches collide to allow both the study of the atomic structure of proteins and their organization in complex networks, both the analysis of microscopic model systems and of patient cohorts, both the screening of small molecules and their development to create affordable drugs.

To join our group as a graduate student or a postdoctoral fellow, please send a motivation letter and a complete CV by email directly to Benoit.Coulombe@ircm.qc.ca. Only candidates of interest will be contacted.

COVID-19

Protein-protein interactions are at the heart of SARS-CoV-2 replication and propagation. The spike glycoprotein interacts with receptors at the surface of host cells to determine viral tropism. The SARS-CoV-2 RNA polymerase associates with other viral proteins to support genome replication and transcription. Our group is studying the function and regulation of protein-protein interactions involved in the SARS-CoV-2 replication cycle.

RARE DISEASES

Mutations causing rare diseases, including leukodystrophies and amyotrophic lateral sclerosis, often perturb interactions of the mutated gene product with cellular partners. Our group is characterizing early protein-protein interaction defects causing rare diseases, and seeking to discover small molecules or peptides to restore these molecular defects.

BIOMARKERS

Protein Affinity Capture coupled to quantitative Mass Spectrometry (PAC-qMS) harnesses the power of antibody-antigen interactions to capture and quantify a protein of interest (antigen) with high specificity and sensitivity. We have developed assays to measure a number of proteins involved in cardiometabolic diseases, including PCSK9 and Insulin, as well as the synaptic adhesion factor neuroligin involved in various types of diseases.

THE PAQOSOME

The Particle for Arrangement of Quaternary structure (PAQosome) plays a crucial role in the assembly of many protein complexes, including RNA polymerases, snRNPs, the ribosome and many others. Our group played a central role in human PAQosome discovery and continues to study its function and regulation.

10 MOST SIGNIFICANT DISCOVERIES FROM OUR LAB

1998: The Promoter DNA Wrapping Model

Robert F, Douziech M, Forget D, Egly JM, Greenblatt J, Burton ZF, Coulombe B.

Wrapping of promoter DNA around the RNA polymerase II initiation complex induced by TFIIF.

Mol Cell. 1998 Sep;2(3):341-51.

2007: The RNA polymerase II interactome and RNA Polymerase II-Associated Proteins (RPAPs)

Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, Thérien C, Bergeron D, Bourassa S, Greenblatt J, Chabot B, Poirier GG, Hughes TR, Blanchette M, Price DH, Coulombe B.

Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.

Mol Cell. 2007 Jul 20;27(2):262-74.

2013: A Novel Family of Lysine Methyltransferases That Target Molecular Chaperones

Cloutier P, Lavallée-Adam M, Faubert D, Blanchette M, Coulombe B.

A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.

PLoS Genet. 2013;9(1):e1003210.

2015: Leukodystrophy-Causing Mutations Impair RNA polymerase III Biogenesis

Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates JR 3rd, Coulombe B, Bernard G.

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Nat Commun. 2015 Jul 7;6:7623.

2017: The R2TP/PFD-like Complex Regulates Assembly of the U5 snRNP and TSC complex

Cloutier P, Poitras C, Durand M, Hekmat O, Fiola-Masson É, Bouchard A, Faubert D, Chabot B, Coulombe B.

R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein.

Nat Commun. 2017 May 31;8:15615.

2018: The Particle for Arrangement of Quaternary structure (PAQosome)

Houry WA, Bertrand E, Coulombe B.

The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation.

Trends Biochem Sci. 2018 Jan;43(1):4-9.

2018: A Model for Interactome Wiring by the PAQosome

Coulombe B, Cloutier P, Gauthier MS.

How do our cells build their protein interactome?

Nat Commun. 2018 Jul 27;9(1):2955.

2018: Phosphorylated PCSK9 Is a Potent Biomarker for Various Diseases

Gauthier MS, Awan Z, Bouchard A, Champagne J, Tessier S, Faubert D, Chabot K, Garneau PY, Rabasa-Lhoret R, Seidah NG, Ridker PM, Genest J, Coulombe B.

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics.

J Clin Lipidol. 2018 Jul-Aug;12(4):1027-1038.

2018: Mutations in the Glutamyl-Prolyl-tRNA Synthetase Gene Cause a Hypomyelinating Leukodystrophy

Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS, Gauquelin L, Tran LT, Forget D, Gauthier MS, Waisfisz Q, Smith DEC, Simons C, van der Knaap MS, Marquardt I, Lemes A, Mierzewska H, Weschke B, Koehler W, Coulombe B, Wolf NI, Bernard G.

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.

Am J Hum Genet. 2018 Apr 5;102(4):676-684.

2020: Complete Subunit Composition of the PAQosome

Cloutier P, Poitras C, Faubert D, Bouchard A, Blanchette M, Gauthier MS, Coulombe B.

Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subunit of the PAQosome.

J Proteome Res. 2020 Jan 3;19(1):18-27.

 
 

TEAM

Dr. Benoit Coulombe
Dr. Benoit Coulombe
Director
Dr. Marie-Soleil Gauthier
Dr. Marie-Soleil Gauthier
Senior Associate Researcher
maxime_pinard_small.png
Dr. Maxime Pinard
Associate Researcher
esen_sokullu.png
Dr. Esen Sokullu
Postdoctoral Fellow
Christian Poitras
Christian Poitras
Systems Analyst
Alexa Derksen
Alexa Derksen
Master Degree Student (Dr. G. Bernard)
Golden Marble
Vijaya Madhoo
Administrative Assistant
Diane Forget
Diane Forget
Honorary Lab Member

2020-06-26 :

Diane Forget prend sa retraite après 27 ans de service dévoué pour le laboratoire. Elle a eu

une contribution exceptionnelle pour nos publications, la formation de personnel, l'administration des fonds de recherche et la planification des espaces de laboratoire. Avec toute notre reconnaissance, merci et bonne continuation.

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