Avak Kahvejian

Flagship Pioneering (United States)

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Nahum Sonenberg

McGill University

Grégory De Crescenzo

Polytechnique Montréal

Kianoush Khaleghpour

McGill University

Yuri V. Svitkin

McGill University

Kalle Gehring

McGill University

Guennadi Kozlov

McGill University

Maureen D. O'Connor‐McCourt

Micropharma (Canada)

Jean‐François Trempe

McGill University

Irena Ekiel

National Research Council Canada

Hiroaki Imataka

University of Hyogo

Cooperative Institutions

McGill University

Harvard University

Helicos Biosciences (United States)

Rubius Therapeutics (United States)

McGill University Health Centre

The University of Texas Health Science Center at Houston

The University of Texas at Austin

Howard Hughes Medical Institute

Ark Therapeutic (United States)

Biotechnology Research Institute

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Structural basis of ligand recognition by PABC, a highly specific peptide-binding domain found in poly(A)-binding protein and a HECT ubiquitin ligase

The EMBO Journal (2003)

Guennadi Kozlov Grégory De Crescenzo Nadia S Lim Nadeem Siddiqui Daniel Fantus

Ubiquitin-Protein Ligases

10.1038/sj.emboj.7600048

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Citations (107)

Poly(A)-Binding Protein Binds to A-Rich Sequences via RNA-Binding Domains 1+2 and 3+4

RNA Biology (2006)

Tasneem Khanam Ravi S. Muddashetty Avak Kahvejian Nahum Sonenberg Juergen Brosius

AbstractPoly(A) binding protein (PABP) binds non-protein-coding BC1 RNA and BC200 RNA, which contain adenosine-rich domains. Two combinations of the four PABP RNA recognition motifs (RRMs), RRMs 1+2 and RRMs 3+4, bind with very strong affinities to various transcripts with long stretches of adenosine residues, whereas RRMs 2+3 bind weakly. While RRMs 1+2 preferentially bind to stretches that contain only adenosines, RRMs 3+4 exhibit relatively high affinities towards sequences that are interspersed with other nucleotides. Binding studies with oligoribonucleotide(A)65 and oligoribonucleotide(A)25 showed that the shorter RNA is not an ideal substrate for binding studies to model the interactions with mRNAs, which in general harbor long poly(A) tails.

10.4161/rna.3.4.4075

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Citations (40)

The mRNA Closed-loop Model: The Function of PABP and PABP-interacting Proteins in mRNA Translation

Cold Spring Harbor Symposia on Quantitative Biology (2001)

Avak Kahvejian Gilles Roy Nahum Sonenberg

Translational control is an important means by whichcells govern gene expression. It provides a rapid responseto growth and proliferation stimuli and plays a role incontrolling feedback mechanisms in the cell. In systemswith little or no transcriptional control (e.g., reticulocytesand oocytes), translation is the predominant mode of regulation of gene expression (for review, see Mathews et al.2000). Initiation, the rate-limiting step of translation, isoften the target of translational control. All nuclear-transcribed eukaryotic mRNAs possess a 5′ cap (m7GpppN,where m is a methyl group and N is any nucleotide), andmost possess a 3′ poly(A) tail. The focus of this paper isthe role of the poly(A) tail and the poly(A)-binding protein (PABP) in translation initiation. Such an analysis requires a brief introduction of translation initiation and itscontrol...

Poly(N-isopropylacrylamide)

Eukaryotic translation

Translational regulation

10.1101/sqb.2001.66.293

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Citations (180)

Paip1 Interacts with Poly(A) Binding Protein through Two Independent Binding Motifs

Molecular and Cellular Biology (2002)

Guylaine Roy Grégory De Crescenzo Kianoush Khaleghpour Avak Kahvejian Maureen D. O'Connor‐McCourt

The 3′ poly(A) tail of eukaryotic mRNAs plays an important role in the regulation of translation. The poly(A) binding protein (PABP) interacts with eukaryotic initiation factor 4G (eIF4G), a component of the eIF4F complex, which binds to the 5′ cap structure. The PABP-eIF4G interaction brings about the circularization of the mRNA by joining its 5′ and 3′ termini, thereby stimulating mRNA translation. The activity of PABP is regulated by two interacting proteins, Paip1 and Paip2. To study the mechanism of the Paip1-PABP interaction, far-Western, glutathione S-transferase pull-down, and surface plasmon resonance experiments were performed. Paip1 contains two binding sites for PABP, PAM1 and PAM2 (for PABP-interacting motifs 1 and 2). PAM2 consists of a 15-amino-acid stretch residing in the N terminus, and PAM1 encompasses a larger C-terminal acidic-amino-acid-rich region. PABP also contains two Paip1 binding sites, one located in RNA recognition motifs 1 and 2 and the other located in the C-terminal domain. Paip1 binds to PABP with a 1:1 stoichiometry and an apparent Kd of 1.9 nM.

EIF4G

Poly(N-isopropylacrylamide)

10.1128/mcb.22.11.3769-3782.2002

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Citations (142)

Poly(A)-binding protein interaction with elF4G stimulates picornavirus IRES-dependent translation.

PubMed (2001)

Yuri V. Svitkin Hiroaki Imataka Kianoush Khaleghpour Avak Kahvejian Hans Liebig

The eukaryotic mRNA 3' poly(A) tail and the 5' cap cooperate to synergistically enhance translation. This interaction is mediated, at least in part, by elF4G, which bridges the mRNA termini by simultaneous binding the poly(A)-binding protein (PABP) and the cap-binding protein, elF4E. The poly(A) tail also stimulates translation from the internal ribosome binding sites (IRES) of a number of picornaviruses. elF4G is likely to mediate this translational stimulation through its direct interaction with the IRES. Here, we support this hypothesis by cleaving elF4G to separate the PABP-binding site from the portion that promotes internal initiation. elF4G cleavage abrogates the stimulatory effect of poly(A) tail on translation. In addition, translation in extracts in which elF4G is cleaved is resistant to inhibition by the PABP-binding protein 2 (Paip2). The elF4G cleavage-induced loss of the stimulatory effect of poly(A) on translation was mimicked by the addition of the C-terminal portion of elF4G. Thus, PABP stimulates picornavirus translation through its interaction with elF4G.

Poly(N-isopropylacrylamide)

Picornavirus

Cleavage (geology)

Eukaryotic translation

EIF4E

EIF4G

Source

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Citations (140)

Single-step capture and sequencing of natural DNA for detection of BRCA1 mutations

Genome Research (2011)

John F. Thompson Jeffrey G. Reifenberger Eldar Giladi Kristen Kerouac Jaime Gill

Genetic testing for disease risk is an increasingly important component of medical care. However, testing can be expensive, which can lead to patients and physicians having limited access to the genetic information needed for medical decisions. To simplify DNA sample preparation and lower costs, we have developed a system in which any gene can be captured and sequenced directly from human genomic DNA without amplification, using no proteins or enzymes prior to sequencing. Extracted whole-genome DNA is acoustically sheared and loaded in a flow cell channel for single-molecule sequencing. Gene isolation, amplification, or ligation is not necessary. Accurate and low-cost detection of DNA sequence variants is demonstrated for the BRCA1 gene. Disease-causing mutations as well as common variants from well-characterized samples are identified. Single-molecule sequencing generates very reproducible coverage patterns, and these can be used to detect any size insertion or deletion directly, unlike PCR-based methods, which require additional assays. Because no gene isolation or amplification is required for sequencing, the exceptionally low costs of sample preparation and analysis could make genetic tests more accessible to those who wish to know their own disease susceptibility. Additionally, this approach has applications for sequencing integration sites for gene therapy vectors, transposons, retroviruses, and other mobile DNA elements in a more facile manner than possible with other methods.

Multiple displacement amplification

Sequencing by ligation

Single cell sequencing

10.1101/gr.122192.111

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Citations (24)

Global genome analysis reveals a vast and dynamic anellovirus landscape within the human virome

Cell Host & Microbe (2021)

Cesar Arze Simeon Springer Gytis Dudas Sneha Patel Agamoni Bhattacharyya

Anelloviruses are a ubiquitous component of healthy human viromes and remain highly prevalent after being acquired early in life. The full extent of "anellome" diversity and its evolutionary dynamics remain unexplored. We employed in-depth sequencing of blood-transfusion donor(s)-recipient pairs coupled with public genomic resources for a large-scale assembly of anellovirus genomes and used the data to characterize global and personal anellovirus diversity through time. The breadth of the anellome is much greater than previously appreciated, and individuals harbor unique anellomes and transmit lineages that can persist for several months within a diverse milieu of endemic host lineages. Anellovirus sequence diversity is shaped by extensive recombination at all levels of divergence, hindering traditional phylogenetic analyses. Our findings illuminate the transmission dynamics and vast diversity of anelloviruses and set the foundation for future studies to characterize their biology.

Human virome

Lineage (genetic)

10.1016/j.chom.2021.07.001

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Citations (74)

True Single Molecule Sequencing (tSMS)™ by Synthesis

Scott A. Jenkins Avak Kahvejian

This chapter contains sections titled: Introduction Methods, Protocols, and Technical Principles Applications Perspectives References

10.1002/9783527629398.ch17

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Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms

Genes & Development (2005)

Avak Kahvejian Yuri V. Svitkin Rami Sukarieh Marie-Noël M’Boutchou Nahum Sonenberg

Translation initiation is a multistep process involving several canonical translation factors, which assemble at the 5′-end of the mRNA to promote the recruitment of the ribosome. Although the 3′ poly(A) tail of eukaryotic mRNAs and its major bound protein, the poly(A)-binding protein (PABP), have been studied extensively, their mechanism of action in translation is not well understood and is confounded by differences between in vivo and in vitro systems. Here, we provide direct evidence for the involvement of PABP in key steps of the translation initiation pathway. Using a new technique to deplete PABP from mammalian cell extracts, we show that extracts lacking PABP exhibit dramatically reduced rates of translation, reduced efficiency of 48S and 80S ribosome initiation complex formation, and impaired interaction of eIF4E with the mRNA cap structure. Supplementing PABP-depleted extracts with wild-type PABP completely rectified these deficiencies, whereas a mutant of PABP, M161A, which is incapable of interacting with eIF4G, failed to restore translation. In addition, a stronger inhibition (approximately twofold) of 80S as compared to 48S ribosome complex formation (∼65% vs. ∼35%, respectively) by PABP depletion suggests that PABP plays a direct role in 60S subunit joining. PABP can thus be considered a canonical translation initiation factor, integral to initiation complex formation at the 5′-end of mRNA.

EIF4G

Poly(N-isopropylacrylamide)

EIF4E

Eukaryotic initiation factor

Eukaryotic translation

Initiation factor

Eukaryotic Ribosome

EIF4A1

10.1101/gad.1262905

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Citations (488)

SOLUTION STRUCTURE OF THE PABC DOMAIN OF HUMAN POLY(A) BINDING PROTEIN

Guennadi Kozlov Jean‐François Trempe Kianoush Khaleghpour Avak Kahvejian Irena Ekiel

10.2210/pdb1g9l/pdb

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