@article{pmid39156973,

title = {The fragile X proteins' enigma: to be or not to be nucleolar},

author = {Edouard W Khandjian and Tom Moss and Timothy M Rose and Claude Robert and Laetitia Davidovic},

doi = {10.3389/fcell.2024.1448209},

issn = {2296-634X},

year  = {2024},

date = {2024-01-01},

journal = {Front Cell Dev Biol},

volume = {12},

pages = {1448209},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36445258,

title = {Roles of the cumulus-oocyte transzonal network and the Fragile X protein family in oocyte competence},

author = {Elolo Karen Nenonene and Mallorie Trottier-Lavoie and Mathilde Marchais and Alexandre Bastien and Isabelle Gilbert and Angus D Macaulay and Edouard W Khandjian and Alberto Maria Luciano and Valentina Lodde and Robert S Viger and Claude Robert},

doi = {10.1530/REP-22-0165},

issn = {1741-7899},

year  = {2023},

date = {2023-02-01},

journal = {Reproduction},

volume = {165},

number = {2},

pages = {209--219},

abstract = {IN BRIEF: RNA granules travel through the cumulus cell network of transzonal projections which is associated with oocyte developmental competence, and RNA packaging involves RNA-binding proteins of the Fragile X protein family.nnABSTRACT: The determinants of oocyte developmental competence have puzzled scientists for decades. It is known that follicular conditions can nurture the production of a high-quality oocyte, but the underlying mechanisms remain unknown. Somatic cumulus cells most proximal to the oocyte are known to have cellular extensions that reach across the zona pellucida and contact with the oocyte plasma membrane. Herein, it was found that transzonal projections (TZPs) network quality is associated with developmental competence. Knowing that ribonucleoparticles are abundant within TZPs, the distribution of RNA-binding proteins was studied. The Fragile X-related proteins (FXR1P and FXR2P) and two partnering protein families, namely cytoplasmic FMRP-interacting protein and nuclear FMRP-interacting protein, exhibited distinctive patterns consistent with roles in regulating mRNA packaging, transport, and translation. The expression of green fluorescent protein (GFP)-FMRP fusion protein in cumulus cells showed active granule formation and their transport and transfer through filipodia connecting with neighboring cells. Near the projections' ends was found the cytoskeletal anchoring protein Filamin A and active protein synthesis sites. This study highlights key proteins involved in delivering mRNA to the oocyte. Thus, cumulus cells appear to indeed support the development of high-quality oocytes via the transzonal network.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36035132,

title = {FMRP, a multifunctional RNA-binding protein in quest of a new identity},

author = {Edouard W Khandjian and Claude Robert and Laetitia Davidovic},

doi = {10.3389/fgene.2022.976480},

issn = {1664-8021},

year  = {2022},

date = {2022-01-01},

journal = {Front Genet},

volume = {13},

pages = {976480},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32365111,

title = {Treatment of cancer cells with Lapatinib negatively regulates general translation and induces stress granules formation},

author = {Pauline Adjibade and Bryan Simoneau and Nassim Ledoux and William-Naud Gauthier and Melisse Nkurunziza and Edouard W Khandjian and Rachid Mazroui},

doi = {10.1371/journal.pone.0231894},

issn = {1932-6203},

year  = {2020},

date = {2020-01-01},

journal = {PLoS One},

volume = {15},

number = {5},

pages = {e0231894},

abstract = {Stress granules (SG) are cytoplasmic RNA granules that form during various types of stress known to inhibit general translation, including oxidative stress, hypoxia, endoplasmic reticulum stress (ER), ionizing radiations or viral infection. Induction of these SG promotes cell survival in part through sequestration of proapoptotic molecules, resulting in the inactivation of cell death pathways. SG also form in cancer cells, but studies investigating their formation upon treatment with chemotherapeutics are very limited. Here we identified Lapatinib (Tykerb / Tyverb®), a tyrosine kinase inhibitor used for the treatment of breast cancers as a new inducer of SG in breast cancer cells. Lapatinib-induced SG formation correlates with the inhibition of general translation initiation which involves the phosphorylation of the translation initiation factor eIF2α through the kinase PERK. Disrupting PERK-SG formation by PERK depletion experiments sensitizes resistant breast cancer cells to Lapatinib. This study further supports the assumption that treatment with anticancer drugs activates the SG pathway, which may constitute an intrinsic stress response used by cancer cells to resist treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26556863,

title = {Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells},

author = {Pauline Adjibade and Valérie Grenier St-Sauveur and Miguel Quevillon Huberdeau and Marie-Josée Fournier and Andreanne Savard and Laetitia Coudert and Edouard W Khandjian and Rachid Mazroui},

doi = {10.18632/oncotarget.5980},

issn = {1949-2553},

year  = {2015},

date = {2015-12-01},

journal = {Oncotarget},

volume = {6},

number = {41},

pages = {43927--43943},

abstract = {Stress granules (SGs) are cytoplasmic RNA multimeric bodies that form under stress conditions known to inhibit translation initiation. In most reported stress cases, the formation of SGs was associated with the cell recovery from stress and survival. In cells derived from cancer, SGs formation was shown to promote resistance to either proteasome inhibitors or 5-Fluorouracil used as chemotherapeutic agents. Despite these studies, the induction of SGs by chemotherapeutic drugs contributing to cancer cells resistance is still understudied. Here we identified sorafenib, a tyrosine kinase inhibitor used to treat hepatocarcinoma, as a potent chemotherapeutic inducer of SGs. The formation of SGs in sorafenib-treated hepatocarcionoma cells correlates with inhibition of translation initiation; both events requiring the phosphorylation of the translation initiation factor eIF2α. Further characterisation of the mechanism of sorafenib-induced SGs revealed PERK as the main eIF2α kinase responsible for SGs formation. Depletion experiments support the implication of PERK-eIF2α-SGs pathway in hepatocarcinoma cells resistance to sorafenib. This study also suggests the existence of an unexpected complex regulatory balance between SGs and phospho-eIF2α where SGs dampen the activation of the phospho-eIF2α-downstream ATF4 cell death pathway.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25143353,

title = {The gametic synapse: RNA transfer to the bovine oocyte},

author = {Angus D Macaulay and Isabelle Gilbert and Julieta Caballero and Rodrigo Barreto and Eric Fournier and Prudencio Tossou and Marc-André Sirard and Hugh J Clarke and Édouard W Khandjian and Francois J Richard and Poul Hyttel and Claude Robert},

doi = {10.1095/biolreprod.114.119867},

issn = {1529-7268},

year  = {2014},

date = {2014-10-01},

journal = {Biol Reprod},

volume = {91},

number = {4},

pages = {90},

abstract = {Even after several decades of quiescent storage in the ovary, the female germ cell is capable of reinitiating transcription to build the reserves that are essential to support early embryonic development. In the current model of mammalian oogenesis, there exists bilateral communication between the gamete and the surrounding cells that is limited to paracrine signaling and direct transfer of small molecules via gap junctions existing at the end of the somatic cells' projections that are in contact with the oolemma. The purpose of this work was to explore the role of cumulus cell projections as a means of conductance of large molecules, including RNA, to the mammalian oocyte. By studying nascent RNA with confocal and transmission electron microscopy in combination with transcript detection, we show that the somatic cells surrounding the fully grown bovine oocyte contribute to the maternal reserves by actively transferring large cargo, including mRNA and long noncoding RNA. This occurrence was further demonstrated by the reconstruction of cumulus-oocyte complexes with transfected cumulus cells transferring a synthetic transcript. We propose selective transfer of transcripts occurs, the delivery of which is supported by a remarkable synapselike vesicular trafficking connection between the cumulus cells and the gamete. This unexpected exogenous contribution to the maternal stores offers a new perspective on the determinants of female fertility.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25409157,

title = {UVC-induced stress granules in mammalian cells},

author = {Mohamed Taha Moutaoufik and Rachid El Fatimy and Hassan Nassour and Cristina Gareau and Jérôme Lang and Robert M Tanguay and Rachid Mazroui and Edouard W Khandjian},

doi = {10.1371/journal.pone.0112742},

issn = {1932-6203},

year  = {2014},

date = {2014-01-01},

journal = {PLoS One},

volume = {9},

number = {11},

pages = {e112742},

abstract = {Stress granules (SGs) are well characterized cytoplasmic RNA bodies that form under various stress conditions. We have observed that exposure of mammalian cells in culture to low doses of UVC induces the formation of discrete cytoplasmic RNA granules that were detected by immunofluorescence staining using antibodies to RNA-binding proteins. UVC-induced cytoplasmic granules are not Processing Bodies (P-bodies) and are bone fide SGs as they contain TIA-1, TIA-1/R, Caprin1, FMRP, G3BP1, PABP1, well known markers, and mRNA. Concomitant with the accumulation of the granules in the cytoplasm, cells enter a quiescent state, as they are arrested in G1 phase of the cell cycle in order to repair DNA damages induced by UVC irradiation. This blockage persists as long as the granules are present. A tight correlation between their decay and re-entry into S-phase was observed. However the kinetics of their formation, their low number per cell, their absence of fusion into larger granules, their persistence over 48 hours and their slow decay, all differ from classical SGs induced by arsenite or heat treatment. The induction of these SGs does not correlate with major translation inhibition nor with phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). We propose that a restricted subset of mRNAs coding for proteins implicated in cell cycling are removed from the translational apparatus and are sequestered in a repressed form in SGs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24204304,

title = {Nuclear Fragile X Mental Retardation Protein is localized to Cajal bodies},

author = {Alain Y Dury and Rachid El Fatimy and Sandra Tremblay and Timothy M Rose and Jocelyn Côté and Paul De Koninck and Edouard W Khandjian},

doi = {10.1371/journal.pgen.1003890},

issn = {1553-7404},

year  = {2013},

date = {2013-10-01},

journal = {PLoS Genet},

volume = {9},

number = {10},

pages = {e1003890},

abstract = {Fragile X syndrome is caused by loss of function of a single gene encoding the Fragile X Mental Retardation Protein (FMRP). This RNA-binding protein, widely expressed in mammalian tissues, is particularly abundant in neurons and is a component of messenger ribonucleoprotein (mRNP) complexes present within the translational apparatus. The absence of FMRP in neurons is believed to cause translation dysregulation and defects in mRNA transport essential for local protein synthesis and for synaptic development and maturation. A prevalent model posits that FMRP is a nucleocytoplasmic shuttling protein that transports its mRNA targets from the nucleus to the translation machinery. However, it is not known which of the multiple FMRP isoforms, resulting from the numerous alternatively spliced FMR1 transcripts variants, would be involved in such a process. Using a new generation of anti-FMRP antibodies and recombinant expression, we show here that the most commonly expressed human FMRP isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only isoforms that localized to the nuclei in cultured human cells. These isoforms localized to specific p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of Fragile X Syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23136128,

title = {A novel function for the survival motoneuron protein as a translational regulator},

author = {Gabriel Sanchez and Alain Y Dury and Lyndsay M Murray and Olivier Biondi and Helina Tadesse and Rachid El Fatimy and Rashmi Kothary and Frédéric Charbonnier and Edouard W Khandjian and Jocelyn Côté},

doi = {10.1093/hmg/dds474},

issn = {1460-2083},

year  = {2013},

date = {2013-02-01},

journal = {Hum Mol Genet},

volume = {22},

number = {4},

pages = {668--684},

abstract = {SMN1, the causative gene for spinal muscular atrophy (SMA), plays a housekeeping role in the biogenesis of small nuclear RNA ribonucleoproteins. SMN is also present in granular foci along axonal projections of motoneurons, which are the predominant cell type affected in the pathology. These so-called RNA granules mediate the transport of specific mRNAs along neurites and regulate mRNA localization, stability, as well as local translation. Recent work has provided evidence suggesting that SMN may participate in the assembly of RNA granules, but beyond that, the precise nature of its role within these structures remains unclear. Here, we demonstrate that SMN associates with polyribosomes and can repress translation in an in vitro translation system. We further identify the arginine methyltransferase CARM1 as an mRNA that is regulated at the translational level by SMN and find that CARM1 is abnormally up-regulated in spinal cord tissue from SMA mice and in severe type I SMA patient cells. We have previously characterized a novel regulatory pathway in motoneurons involving the SMN-interacting RNA-binding protein HuD and CARM1. Thus, our results suggest the existence of a potential negative feedback loop in this pathway. Importantly, an SMA-causing mutation in the Tudor domain of SMN completely abolished translational repression, a strong indication for the functional significance of this novel SMN activity in the pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22737234,

title = {Fragile X mental retardation protein interacts with the RNA-binding protein Caprin1 in neuronal RiboNucleoProtein complexes [corrected]},

author = {Rachid El Fatimy and Sandra Tremblay and Alain Y Dury and Samuel Solomon and Paul De Koninck and John W Schrader and Edouard W Khandjian},

doi = {10.1371/journal.pone.0039338},

issn = {1932-6203},

year  = {2012},

date = {2012-01-01},

journal = {PLoS One},

volume = {7},

number = {6},

pages = {e39338},

abstract = {Fragile X syndrome is caused by the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein. FMRP is associated with messenger RiboNucleoParticles (mRNPs) present in polyribosomes and its absence in neurons leads to alteration in synaptic plasticity as a result of translation regulation defects. The molecular mechanisms by which FMRP plays a role in translation regulation remain elusive. Using immunoprecipitation approaches with monoclonal Ab7G1-1 and a new generation of chicken antibodies, we identified Caprin1 as a novel FMRP-cellular partner. In vivo and in vitro evidence show that Caprin1 interacts with FMRP at the level of the translation machinery as well as in trafficking neuronal granules. As an RNA-binding protein, Caprin1 has in common with FMRP at least two RNA targets that have been identified as CaMKIIα and Map1b mRNAs. In view of the new concept that FMRP species bind to RNA regardless of known structural motifs, we propose that protein interactors might modulate FMRP functions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}