Abstract
Ribonucleoprotein (RNP) complexes form around nascent RNA during transcription to facilitate proper transcriptional elongation, RNA processing, and nuclear export. RNPs are highly heterogeneous, and different types of RNPs tend to package functionally related transcripts. These observations have inspired the hypothesis that RNP mediated mechanisms help specify coordinated gene expression. This hypothesis is supported by the observation that mutations in RNP components can cause defects in specific developmental pathways. How RNP biogenesis itself is regulated, however, is not well understood. The evolutionarily conserved THO RNP complex functions early during transcription to package nascent transcripts and facilitate subsequent RNP biogenesis. THO deficiency compromises transcriptional elongation as well as RNP mediated events like 3′ end formation and nuclear export for some transcripts. Using molecularly manipulated cells and in vitro reconstituted biochemical reactions, we demonstrate that the essential THO protein component encoded by the Thoc1 gene is poly-ubiquitinated by the NEDD4-1 E3 ubiquitin ligase. Poly-ubiquitinated pThoc1 is degraded by the proteasome. These results indicate THO activity is regulated by the ubiquitin-proteasome pathway, and that this regulation is evolutionarily conserved between yeast and mammals. Manipulation of NEDD4-1 levels has modest effects on Thoc1 protein levels under steady state conditions, but destabilization of Thoc1 protein upon treatment with a transcriptional elongation inhibitor is dependent on NEDD4-1. This suggests NEDD4-1 functions in conjunction with other post-translational mechanisms to regulate Thoc1 protein and THO activity.
Highlights
The co-transcriptional packaging of nascent RNA transcripts into RNP complexes is important for transcriptional elongation, RNA processing, and RNA export from the nucleus [1]
The results presented here demonstrate that pThoc1, an essential protein component of the mammalian THO RNP complex, is a substrate for the NEDD4-1 E3 ubiquitin ligase
NEDD4-1 is a member of the HECT catalytic domain E3 ubiquitin ligase family
Summary
The co-transcriptional packaging of nascent RNA transcripts into RNP complexes is important for transcriptional elongation, RNA processing, and RNA export from the nucleus [1]. RNP complexes are composed of multiple protein and RNA subunits. They are heterogeneous and dynamic, differing in composition depending on the transcript and the stage within a transcripts life cycle. Potential combinatorial permutations are vast enough to potentially ensure that each transcript is processed by a unique series of RNP complexes [2]. These observations have inspired the hypothesis that co- and post-transcriptional RNP mediated mechanisms support the elaboration of coordinated gene expression programs [3,4]. While the importance of RNP mediated mechanisms for coordinated gene expression is increasingly appreciated, how RNP biogenesis itself is regulated is not well understood
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