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See detailIdentification et caractérisation des sous-unités ELP5 et ELP6 du complexe Elongator humain
Gillard, Magali ULg

Doctoral thesis (2013)

Familial Dysautonomia is a neurodegenerative disorder that affects the autonomic and sensory nervous systems. This disease results from loss-of-function mutations of the ELP1-encoding gene. ELP1 is ... [more ▼]

Familial Dysautonomia is a neurodegenerative disorder that affects the autonomic and sensory nervous systems. This disease results from loss-of-function mutations of the ELP1-encoding gene. ELP1 is required for the integrity of the so-called Elongator complex, which is composed of two sub-proteins complexes, namely the core-Elongator (ELP1 to ELP3) and HAP (ELP4 to ELP6). While ELP3 is acting as an acetyltransferase that target multiple substrates such as nuclear histones and cytoplasmic α-tubulin, the ELP4-6 has been recently described as an ATPase. This complex has been initially identified as a component of a hyperphosphorylated RNA polymerase II holoenzyme. As a result, Elongator is involved in transcriptional elongation. Since, other roles have been assigned. Elongator is indeed also required for some tRNA modifications in the cytoplasm and consequently controls translation fidelity. Those molecular functions underlie the capacity of Elongator to regulate cell division, DNA-damage response and cell motility. It is likely that a better understanding of the molecular functions of Elongator will clarify its role in these cellular processes and probably highlight new features. The identity of human ELP1 through ELP4 has been reported but human ELP5 and ELP6 have remained uncharacterized. We therefore initiated a study dedicated to the identification and characterization of both proteins. A biochemical purification of ELP4 was conducted to isolate all associated proteins. Such experimental approach led to the identification of DERP6 and C3ORF75 as human ELP5 and ELP6 subunits of the Elongator complex, respectively. We further investigated the cellular functions of both subunits by combining biochemical analysis and cellular assays. Our results show that DERP6/Elp5 is required for the integrity and the fucntion of Elongator and directly connects ELP3 to ELP4. Our laboratory has previously demonstrated the key role of Elongator in cell migration. As cell motility is required for cell invasion and metastasis, we therefore investigated to which extent Elongator is involved in those processes. The migration and tumorigenicity of melanoma-derived cells are significantly decreased upon Elongator invalidation through Elp1 or Elp3 depletion. Strikingly, DERP6/Elp5 and C3ORF75/Elp6-depleted melanoma cells have similar defects, further supporting the idea that DERP6/Elp5 and C3ORF75/Elp6 are essential for Elongator function. Together, our data identify DERP6/ELP5 and C3ORF75/ELP6 as key players for migration, invasion and tumorigenicity of melanoma cells, as integral subunits of Elongator. [less ▲]

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See detailThe emerging role of lysine acetylation of non-nuclear proteins
Close, Pierre ULg; Creppe, Catherine; Gillard, Magali ULg et al

in Cellular and Molecular Life Sciences : CMLS (2010), 67(8), 1255-1264

Lysine acetylation is a post-translational modification that critically regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus. More recent reports ... [more ▼]

Lysine acetylation is a post-translational modification that critically regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus. More recent reports have also demonstrated that numerous proteins located outside the nucleus are also acetylated and that this modification has profound consequences on their functions. This review describes the latest findings on the substrates acetylated outside the nucleus and on the acetylases and deacetylates that catalyse these modifications. Protein acetylation is emerging as a major mechanism by which key proteins are regulated in many physiological processes such as migration, metabolism and aging as well as in pathological circumstances such as cancer and neurodegenerative disorders. [less ▲]

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See detailElongator orchestrates cerebral cortical neurogenesis
creppe, catherine; malinouskaya, lina; Volvert, Marie-Laure ULg et al

in Medecine Sciences : M/S (2010)

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See detailElongator controls the migration and differentiation of cortical neurons through acetylation of a tubulin
Creppe, Catherine ULg; Malinouskaya, Lina ULg; Volvert, Marie-Laure ULg et al

in Cell (2009), 136

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which ... [more ▼]

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha tubulin. A direct reduction of alpha tubulin acetylation leads to comparable defects in cortical neurons and suggests that alpha tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons. [less ▲]

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See detailDeregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells.
Cornez, Isabelle ULg; Creppe, Catherine ULg; Gillard, Magali ULg et al

in Biochemical Pharmacology (2008), 75

Elongator, a multi-subunit complex assembled by the IkappaB kinase-associated protein (IKAP)/hELP1 scaffold protein is involved in transcriptional elongation in the nucleus as well as in tRNA ... [more ▼]

Elongator, a multi-subunit complex assembled by the IkappaB kinase-associated protein (IKAP)/hELP1 scaffold protein is involved in transcriptional elongation in the nucleus as well as in tRNA modifications in the cytoplasm. However, the biological processes regulated by Elongator in human cells only start to be elucidated. Here we demonstrate that IKAP/hELP1 depleted colon cancer-derived cells show enhanced basal expression of some but not all pro-apoptotic p53-dependent genes such as BAX. Moreover, Elongator deficiency causes increased basal and daunomycin-induced expression of the pro-survival serum- and glucocorticoid-induced protein kinase (SGK) gene through a p53-dependent pathway. Thus, our data collectively demonstrate that Elongator deficiency triggers the activation of p53-dependent genes harbouring opposite functions with respect to apoptosis. [less ▲]

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