Marius Boulos Faza

ETH Zurich, Zürich, Zurich, Switzerland

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Publications (5)32.95 Total impact

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    ABSTRACT: eLife digest Plants, fungi, and animals store their genetic material within the nucleus of each of their cells. This structure is surrounded by a double layer of membrane that prevents the contents of the nucleus from mixing with the contents of the rest of the cell (namely the cytoplasm). Exchange of material between the nucleus and cytoplasm occurs through pores embedded within the nuclear membrane. To travel through one of these pores, large molecules (also called cargos) require the assistance of so-called ‘transport receptors’ such as the Crm1 protein. This protein recognizes and binds to the part of a cargo molecule called a ‘nuclear export signal’, and the Crm1 protein also binds to another protein called RanGTP. Nuclear export signals bind weakly to Crm1, which in turn ensures that these cargos are easily released in the cytoplasm once transport is completed. However, this weak binding means that it has remained a mystery how Crm1 is able to efficiently transport cargos out of the nucleus to begin with. Now, Fischer et al. have analyzed how one cargo that contains a nuclear export signal, namely molecules called ribosome precursors, assembles with Crm1. The experiments identified another protein called Slx9 that shuttles rapidly between the inside and the outside of the nucleus. Fischer et al. observed that Slx9 binds directly to RanGTP and brings it together with the ribosome precursor cargo. When a complex of Slx9, RanGTP, and cargo is assembled, it further recruits Crm1 to the cargo. Thus, Slx9 acts as a scaffold to bring cargo into contact with Crm1 and RanGTP, and a tight complex is formed that enables the export of the cargo out of the nucleus. Yeast cells lacking Slx9 delay export of ribosome precursors out of the nucleus. These findings imply the existence of yet-unidentified proteins like Slx9 that help Crm1 to rapidly transport diverse cargos out from the nucleus and into the cytoplasm. DOI: http://dx.doi.org/10.7554/eLife.05745.002
    Full-text · Article · Apr 2015 · eLife Sciences
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    ABSTRACT: Nuclear export of mRNAs and pre-ribosomal subunits (pre40S and pre60S) is fundamental to all eukaryotes. While genetic approaches in budding yeast have identified bona fide export factors for mRNAs and pre60S subunits, little is known regarding nuclear export of pre40S subunits. The yeast heterodimeric transport receptor Mex67-Mtr2 (TAP-p15 in humans) binds mRNAs and pre60S subunits in the nucleus and facilitates their passage through the nuclear pore complex (NPC) into the cytoplasm by interacting with Phe-Gly (FG)-rich nucleoporins that line its transport channel. By exploiting a combination of genetic, cell-biological, and biochemical approaches, we uncovered an unanticipated role of Mex67-Mtr2 in the nuclear export of 40S pre-ribosomes. We show that recruitment of Mex67-Mtr2 to pre40S subunits requires loops emanating from its NTF2-like domains and that the C-terminal FG-rich nucleoporin interacting UBA-like domain within Mex67 contributes to the transport of pre40S subunits to the cytoplasm. Remarkably, the same loops also recruit Mex67-Mtr2 to pre60S subunits and to the Nup84 complex, the respective interactions crucial for nuclear export of pre60S subunits and mRNAs. Thus Mex67-Mtr2 is a unique transport receptor that employs a common interaction surface to participate in the nuclear export of both pre-ribosomal subunits and mRNAs. Mex67-Mtr2 could engage a regulatory crosstalk among the three major export pathways for optimal cellular growth and proliferation.
    Full-text · Article · Aug 2012 · PLoS Genetics
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    ABSTRACT: The hypoxia-inducible transcription factor (HIF) is a key component of the cellular adaptation mechanisms to hypoxic conditions. HIFα subunits are degraded by prolyl-4-hydroxylase domain (PHD) enzyme-dependent prolyl-4-hydroxylation of LxxLAP motifs that confer oxygen-dependent proteolytic degradation. Interestingly, only three non-HIFα proteins contain two conserved LxxLAP motifs, including the putative RNA helicase with a zinc finger domain HELZ. However, HELZ proteolytic regulation was found to be oxygen-independent, supporting the notion that a LxxLAP sequence motif alone is not sufficient for oxygen-dependent protein destruction. Since biochemical pathways involving RNA often require RNA helicases to modulate RNA structure and activity, we used luciferase reporter gene constructs and metabolic labeling to demonstrate that HELZ overexpression activates global protein translation whereas RNA-interference mediated HELZ suppression had the opposite effect. Although HELZ interacted with the poly(A)-binding protein (PABP) via its PAM2 motif, PABP was dispensable for HELZ function in protein translation. Importantly, downregulation of HELZ reduced translational initiation, resulting in the disassembly of polysomes, in a reduction of cell proliferation and hypophosphorylation of ribosomal protein S6.
    Full-text · Article · Jul 2011 · PLoS ONE
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    Marius Boulos Faza · Stefan Kemmler · Vikram Govind Panse
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    ABSTRACT: The evolutionary conserved protein Sem1/Dss1 is a bona fide subunit of the regulatory particle (RP) of the proteasome and in mammalian cells stabilizes the tumor suppressor protein BRCA2. A recent study from our laboratory has revealed an unexpected non- proteasomal role of Sem1 in mRNA export. We found that Sem1, independent of the RP, is a functional component of the nuclear pore associated TREX-2 complex that is directly involved in the dynamic relocalization of a subset of DNA loci to the nuclear periphery. Like other components of TREX-2, Sem1 is required for proper nuclear export of mRNAs, transcription elongation and preventing transcription-associated genomic instability. Strikingly, Sem1 associates with a third multi-subunit protein complex namely the COP9 signalosome, which is involved in de-neddylation. We propose that Sem1 is a versatile protein that regulates the functional integrity of multiple protein complexes involved in diverse biological pathways.
    Full-text · Article · Jan 2010 · Nucleus (Austin, Texas)
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    ABSTRACT: The evolutionarily conserved protein Sem1/Dss1 is a subunit of the regulatory particle (RP) of the proteasome, and, in mammalian cells, binds the tumor suppressor protein BRCA2. Here, we describe a new function for yeast Sem1. We show that sem1 mutants are impaired in messenger RNA (mRNA) export and transcription elongation, and induce strong transcription-associated hyper-recombination phenotypes. Importantly, Sem1, independent of the RP, is functionally linked to the mRNA export pathway. Biochemical analyses revealed that, in addition to the RP, Sem1 coenriches with components of two other multisubunit complexes: the nuclear pore complex (NPC)-associated TREX-2 complex that is required for transcription-coupled mRNA export, and the COP9 signalosome, which is involved in deneddylation. Notably, targeting of Thp1, a TREX-2 component, to the NPC is perturbed in a sem1 mutant. These findings reveal an unexpected nonproteasomal function of Sem1 in mRNA export and in prevention of transcription-associated genome instability. Thus, Sem1 is a versatile protein that might stabilize multiple protein complexes involved in diverse pathways.
    Full-text · Article · Apr 2009 · The Journal of Cell Biology