Abstract
The Elongator complex is composed of 6 subunits (Elp1-Elp6) and promotes RNAPII transcript elongation through histone acetylation in the nucleus as well as tRNA modification in the cytoplasm. This acetyltransferase complex directly or indirectly regulates numerous biological processes ranging from exocytosis and resistance to heat shock in yeast to cell migration and neuronal differentiation in higher eukaryotes. The identity of human ELP1 through ELP4 has been reported but human ELP5 and ELP6 have remained uncharacterized. Here, we report that DERP6 (ELP5) and C3ORF75 (ELP6) encode these subunits of human Elongator. We further investigated the importance and function of these two subunits by a combination of biochemical analysis and cellular assays. Our results show that DERP6/ELP5 is required for the integrity of Elongator and directly connects ELP3 to ELP4. Importantly, the migration and tumorigenicity of melanoma-derived cells are significantly decreased upon Elongator depletion through ELP1 or ELP3. 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.
Highlights
Elongator is an acetylase complex that regulates cell migration
Identification of derived protein 6 (DERP6) and C3ORF75 as Elongator Subunits—Human Elongator was previously purified from HeLa cells, which led to the identification of ELP1, ELP2, and ELP3 as subunits of the so-called “core” complex [2, 3]
Sequence alignment confirmed that DERP6 and C3ORF75 correspond to human homologues of yeast Elp5 and Elp6, respectively
Summary
Elongator is an acetylase complex that regulates cell migration. Results: DERP6 (ELP5) and C3ORF75 (ELP6) are characterized as Elongator subunits that control cell motility and tumorigenicity of melanoma cells. Our data identify DERP6/ELP5 and C3ORF75/ELP6 as key players for migration, invasion and tumorigenicity of melanoma cells, as integral subunits of Elongator. A substantial fraction of Elongator is cytoplasmic [2, 3, 13], raising the possibility that this complex performs additional molecular functions in the cell [14] In this context, genetic data in yeast demonstrated that Elongator is required for the presence of 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) groups on uridines at the wobble position of some tRNAs [15,16,17]. Our data identify the genes encoding ELP5 and ELP6 in human cells, define Elongator as a key actor for the tumorigenic potential and motility of melanoma cells, and provide further mechanistic insights into the function of DERP6/ELP5
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