Article

To the pore and through the pore: A story of mRNA export kinetics

Faculty of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada H3A 1A3.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2012; 1819(6):494-506. DOI: 10.1016/j.bbagrm.2012.02.011
Source: PubMed

ABSTRACT

The evolutionary 'decision' to store genetic information away from the place of protein synthesis, in a separate compartment, has forced eukaryotic cells to establish a system to transport mRNAs from the nucleus to the cytoplasm for translation. To ensure export to be fast and efficient, cells have evolved a complex molecular interplay that is tightly regulated. Over the last few decades, many of the individual players in this process have been described, starting with the composition of the nuclear pore complex to proteins that modulate co-transcriptional events required to prepare an mRNP for export to the cytoplasm. How the interplay between all the factors and processes results in the efficient and selective export of mRNAs from the nucleus and how the export process itself is executed within cells, however, is still not fully understood. Recent advances in using proteomic and single molecule microscopy approaches have provided important insights into the process and its kinetics. This review summarizes these recent advances and how they led to the current view on how cells orchestrate the export of mRNAs. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.

Download full-text

Full-text

Available from: Marlene Oeffinger, Feb 11, 2014
  • Source
    • "The export of mRNAs from the nucleus to the cytoplasm is one of many steps along the gene expression pathway and is fundamental for mRNAs to meet with ribosomes for translation in the cytoplasm (Oeffinger and Zenklusen, 2012). Export to the cytoplasm occurs through the nuclear pore complex (NPC), a large macromolecular complex embedded in the nuclear membrane (Aitchison and Rout, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: After synthesis and transit through the nucleus, messenger RNAs (mRNAs) are exported to the cytoplasm through the nuclear pore complex (NPC). At the NPC, messenger ribonucleoproteins (mRNPs) first encounter the nuclear basket where mRNP rearrangements are thought to allow access to the transport channel. Here, we use single mRNA resolution live cell microscopy and subdiffraction particle tracking to follow individual mRNAs on their path toward the cytoplasm. We show that when reaching the nuclear periphery, RNAs are not immediately exported but scan along the nuclear periphery, likely to find a nuclear pore allowing export. Deletion or mutation of the nuclear basket proteins MLP1/2 or the mRNA binding protein Nab2 changes the scanning behavior of mRNPs at the nuclear periphery, shortens residency time at nuclear pores, and results in frequent release of mRNAs back into the nucleoplasm. These observations suggest a role for the nuclear basket in providing an interaction platform that keeps RNAs at the periphery, possibly to allow mRNP rearrangements before export.
    Full-text · Article · Dec 2015 · The Journal of Cell Biology
  • Source
    • "NPCs consist of more than two dozen different proteins [132]. These nucleoporins form a channel and regulate the nucleocytoplasmic transport of various types of RNAs [133], and proteins [134]. The nuclear import and export of most proteins >40 KDa in size, including membrane "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Nov 2015 · Seminars in Cancer Biology
  • Source
    • "Gating of active genes at NPCs is not strictly conserved . In mice and humans, for example, a number of developmentally regulated genes move away from the nuclear periphery upon induction, producing mRNA protein complexes that travel through the nucleoplasm to NPCs before export (see references in Egecioglu and Brickner 2011; Oeffinger and Zenklusen 2012). Nevertheless , components of the nuclear pore may still play significant roles in transcription. "
    [Show abstract] [Hide abstract]
    ABSTRACT: tRNAs are encoded by RNA polymerase III-transcribed genes that reside at seemingly random intervals along the chromosomes of budding yeast. Existing evidence suggests that the genes congregate together at the nucleolus and/or centromeres. In this study, we re-examined spatial and temporal aspects of tRNA gene (tDNA) expression. We show that tDNA transcription fluctuates during cell cycle progression. In M phase, when tRNA synthesis peaks, tDNAs localize at nuclear pore complexes (NPCs). Docking of a tDNA requires the DNA sequence of the contacted gene, nucleoporins Nup60 and Nup2, and cohesin. Characterization of mutants that block NPC localization revealed that docking is a consequence of elevated tDNA transcription. NPC-tDNA contact falters in the absence of the principal exportin of nascent tRNA, Los1, and genetic assays indicate that gating of tDNAs at NPCs favors cytoplasmic accumulation of functional tRNA. Collectively, the data suggest that tDNAs associate with NPCs to coordinate RNA polymerase III transcription with the nuclear export of pre-tRNA. The M-phase specificity of NPC contact reflects a regulatory mechanism that may have evolved, in part, to avoid collisions between DNA replication forks and transcribing RNA polymerase III machinery at NPCs.
    Preview · Article · May 2014 · Genes & development
Show more