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      Human Senataxin Resolves RNA/DNA Hybrids Formed at Transcriptional Pause Sites to Promote Xrn2-Dependent Termination

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          Summary

          We present a molecular dissection of pause site-dependent transcriptional termination for mammalian RNA polymerase II (Pol II)-transcribed genes. We show that nascent transcripts form RNA/DNA hybrid structures (R-loops) behind elongating Pol II and are especially prevalent over G-rich pause sites positioned downstream of gene poly(A) signals. Senataxin, a helicase protein associated with AOA2/ALS4 neurodegenerative disorders, acts to resolve these R-loop structures and by so doing allows access of the 5 ′–3 ′ exonuclease Xrn2 at 3 ′ cleavage poly(A) sites. This affords 3 ′ transcript degradation and consequent Pol II termination. In effect, R-loops formed over G-rich pause sites, followed by their resolution by senataxin, are key steps in the termination process.

          Abstract

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          Highlights

          ► Senataxin is required for pause-dependent Pol II termination in human genes ► R-loops accumulate over G-rich pause regions and are required for termination ► R-loops dependent on transcription, functional poly(A) signal, and pause elements ► Senataxin resolves R-loops to allow Xrn2 to mediate Pol II release from the gene

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          DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).

          Ying-Zhang Chen, Craig Bennett, Huy M. Huynh … (2004)
          Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.
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            Loss of Topoisomerase I leads to R-loop-mediated transcriptional blocks during ribosomal RNA synthesis.

            David Tollervey, Audrey French, Ann Beyer … (2010)
            Pre-rRNA transcription by RNA Polymerase I (Pol I) is very robust on active rDNA repeats. Loss of yeast Topoisomerase I (Top1) generated truncated pre-rRNA fragments, which were stabilized in strains lacking TRAMP (Trf4/Trf5-Air1/Air2-Mtr4 polyadenylation complexes) or exosome degradation activities. Loss of both Top1 and Top2 blocked pre-rRNA synthesis, with pre-rRNAs truncated predominately in the 18S 5' region. Positive supercoils in front of Pol I are predicted to slow elongation, while rDNA opening in its wake might cause R-loop formation. Chromatin immunoprecipitation analysis showed substantial levels of RNA/DNA hybrids in the wild type, particularly over the 18S 5' region. The absence of RNase H1 and H2 in cells depleted of Top1 increased the accumulation of RNA/DNA hybrids and reduced pre-rRNA truncation and pre-rRNA synthesis. Hybrid accumulation over the rDNA was greatly exacerbated when Top1, Top2, and RNase H were all absent. Electron microscopy (EM) analysis revealed Pol I pileups in the wild type, particularly over the 18S. Pileups were longer and more frequent in the absence of Top1, and their frequency was exacerbated when RNase H activity was also lacking. We conclude that the loss of Top1 enhances inherent R-loop formation, particularly over the 5' region of the rDNA, imposing persistent transcription blocks when RNase H is limiting.
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              The yeast Rat1 exonuclease promotes transcription termination by RNA polymerase II.

              Minkyu Kim, Nevan Krogan, Lidia Vasiljeva … (2004)
              The carboxy-terminal domain (CTD) of the RNA polymerase II (RNApII) largest subunit consists of multiple heptapeptide repeats with the consensus sequence YSPTSPS. Different CTD phosphorylation patterns act as recognition sites for the binding of various messenger RNA processing factors, thereby coupling transcription and mRNA processing. Polyadenylation factors are co-transcriptionally recruited by phosphorylation of CTD serine 2 (ref. 2) and these factors are also required for transcription termination. RNApII transcribes past the poly(A) site, the RNA is cleaved by the polyadenylation machinery, and the RNA downstream of the cleavage site is degraded. Here we show that Rtt103 and the Rat1/Rai1 5' --> 3' exonuclease are localized at 3' ends of protein coding genes. In rat1-1 or rai1Delta cells, RNA 3' to polyadenylation sites is greatly stabilized and termination defects are seen at many genes. These findings support a model in which poly(A) site cleavage and subsequent degradation of the 3'-downstream RNA by Rat1 trigger transcription termination.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Cell
                Journal ID (iso-abbrev): Mol. Cell
                Title: Molecular Cell
                Publisher: Cell Press
                ISSN (Print): 1097-2765
                ISSN (Electronic): 1097-4164
                Publication date PMC-release: 24 June 2011
                Publication date (Print): 24 June 2011
                Volume: 42
                Issue: 6
                Pages: 794-805
                Affiliations
                [1 ]Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
                Author notes
                [∗ ]Corresponding author nicholas.proudfoot@ 123456path.ox.ac.uk
                [∗∗ ]Corresponding author natalia.gromak@ 123456path.ox.ac.uk
                Article
                Publisher ID: MOLCEL3891
                DOI: 10.1016/j.molcel.2011.04.026
                PMC ID: 3145960
                PubMed ID: 21700224
                SO-VID: 23fa0904-3779-4432-8f6b-cc5378ea84a1
                Copyright © © 2011 ELL & Excerpta Medica.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 4 November 2010
                Date revision received : 10 March 2011
                Date accepted : 18 April 2011
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
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                ScienceOpen disciplines: Molecular biology

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