Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewThe interface between transcription and mRNP export: From THO to THSC/TREX-2
Research Highlights
► THO and THSC play different roles at transcription/mRNA export interface ► Aberrant mRNPs accumulate in THO mutants forming R-loops ► R-loops cause genome instability ► Defects in mRNP biogenesis hinder RNAPII transcription
Section snippets
mRNP biogenesis and the THO complex
THO is a multimeric complex conserved in higher eukaryotes required for mRNP biogenesis. It was initially purified under high-salt conditions as a four-subunit complex formed by Tho2, Hpr1, Mft1 and Thp2 [1]. Isolation of THO in milder conditions pulls down Sub2 and Yra1, two mRNA export factors, and a novel protein termed Tex1 in the so-called TREX (transcription/export) complex [2]. Nevertheless the integrity of the THO complex requires Hpr1, Tho2, Mft1 and Thp2 but not Sub2 [3], [4]. In
Co-transcriptional mRNP formation and R-loops
One important feature of cells lacking the THO complex is that the suboptimal mRNPs produced hinder transcription elongation and generate genome instability measured as an increase in recombination [24]. This is to some extent explained by DNA::RNA hybrid formation. In cells deprived of THO the nascent RNA tends to hybridize more often or strongly with the non-template DNA strand. As a consequence, DNA::RNA hybrids (R-loops) accumulate in THO mutants [24], [25]. The displaced DNA strand is more
Does transcription serve to monitor mRNP formation?
Formation of an export-competent mRNP involves multiple processes that could fail producing aberrant mRNPs. Accumulation of faulty mRNPs might affect transcription in different ways: forming R-loops that would stall RNAPII, impeding RNAPII release from the DNA and therefore blocking elongation of upstream RNAPIIs or activating RNA quality checkpoints (Fig. 2). Although initially studied in the cytoplasm it is now evident that mRNP quality control starts at the nucleus as soon as the RNA is
Connection between 3′ end processing and other mRNP biogenesis steps
The absence of a functional THO hinders multiple mechanisms like transcription elongation and mRNA export making it difficult to infer the direct function of THO from in vivo experiments. Recent results connecting THO with mRNA 3′-end processing, transcription termination and transcript release add complexity to the problem. RNAPII does not transcribe beyond a polyA signal in cells deprived of THO, as seen by transcriptional run-on [54]. This is interpreted as premature termination although
Towards mRNA export via the THSC complex
As mentioned above, most of the phenotypes described in THO mutants are also recapitulated in THSC mutants. This includes the recently described defect in in vitro 3′ end processing and the increase in 3′-end processing factors bound to polyadenylated mRNA [15], [54]. However, there are important differences indicating that both complexes have distinct roles in mRNP biogenesis. First, only THSC interacts with the nuclear pore [33]. Second, an increase of Sub2 levels in THO mutants suppresses
Conclusions and perspectives
The isolation and characterization of THO and THSC complexes among other factors involved in mRNP biogenesis have contributed to outlining the intricate pattern of connections between transcription, mRNA processing and mRNP export. Despite many aspects of the mRNP biogenesis being deciphered, there are still many open questions on how the mRNP assembles and is modified to be exported and translated. Recently purified mRNPs have been visualised for the first time. The subset of mRNPs that
Acknowledgments
We would like to thank R. Luna for critical reading of the manuscript and Diane Haun for style supervision. Research in AA's laboratory is funded by the Spanish Ministry of Science and Innovation and the Junta de Andalucía.
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