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  • 1
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    BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2 (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-06-05
    Description: Genome instability is central to ageing, cancer and other diseases. It is not only proteins involved in DNA replication or the DNA damage response (DDR) that are important for maintaining genome integrity: from yeast to higher eukaryotes, mutations in genes involved in pre-mRNA splicing and in the biogenesis and export of messenger ribonucleoprotein (mRNP) also induce DNA damage and genome instability. This instability is frequently mediated by R-loops formed by DNA-RNA hybrids and a displaced single-stranded DNA. Here we show that the human TREX-2 complex, which is involved in mRNP biogenesis and export, prevents genome instability as determined by the accumulation of gamma-H2AX (Ser-139 phosphorylated histone H2AX) and 53BP1 foci and single-cell electrophoresis in cells depleted of the TREX-2 subunits PCID2, GANP and DSS1. We show that the BRCA2 repair factor, which binds to DSS1, also associates with PCID2 in the cell. The use of an enhanced green fluorescent protein-tagged hybrid-binding domain of RNase H1 and the S9.6 antibody did not detect R-loops in TREX-2-depleted cells, but did detect the accumulation of R-loops in BRCA2-depleted cells. The results indicate that R-loops are frequently formed in cells and that BRCA2 is required for their processing. This link between BRCA2 and RNA-mediated genome instability indicates that R-loops may be a chief source of replication stress and cancer-associated instability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhatia, Vaibhav -- Barroso, Sonia I -- Garcia-Rubio, Maria L -- Tumini, Emanuela -- Herrera-Moyano, Emilia -- Aguilera, Andres -- England -- Nature. 2014 Jul 17;511(7509):362-5. doi: 10.1038/nature13374. Epub 2014 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centro Andaluz de Biologia Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avenida Americo Vespucio s/n, 41092 Seville, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24896180" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyltransferases/metabolism ; BRCA2 Protein/deficiency/genetics/*metabolism ; DNA Damage ; DNA Replication ; DNA, Single-Stranded/chemistry/*metabolism ; Exodeoxyribonucleases/chemistry/deficiency/*metabolism ; *Genomic Instability ; Histones/chemistry/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Nuclear Proteins/*metabolism ; Nucleic Acid Conformation ; Phosphoproteins/chemistry/deficiency/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; RNA/chemistry/*metabolism ; *RNA Transport ; Ribonuclease H/chemistry ; Ribonucleoproteins/biosynthesis/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Topological constraints impair RNA polymerase II transcription and causes instability of plasmid-borne convergent genes (2012)
    Oxford University Press
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    Publication Date: 2012-02-17
    Description: Despite the theoretical bases for the association of topoisomerases and supercoiling changes with transcription and replication, our knowledge of the impact of topological constraints on transcription and replication is incomplete. Although mutation of topoisomerases affects expression and stability of the rDNA region it is not clear whether the same is the case for RNAPII transcription and genome integrity in other regions. We developed new assays in which two convergent RNAPII-driven genes are transcribed simultaneously. Plasmid-based systems were constructed with and without a transcription terminator between the two convergent transcription units, so that the impact of transcription interference could also be evaluated. Using these assays we show that Topos I and II play roles in RNAPII transcription in vivo and reduce the stability of RNAPII-transcribed genes in Saccharomyces cerevisiae . Supercoiling accumulation in convergent transcription units impairs RNAPII transcription in top1 strains, but Topo II is also required for efficient transcription independent of Topo I and of detectable supercoiling accumulation. Our work shows that topological constraints negatively affect RNAPII transcription and genetic integrity, and provides an assay to study gene regulation by transcription interference.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    A genome-wide function of THSC/TREX-2 at active genes prevents transcription-replication collisions (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: The THSC/TREX-2 complex of Saccharomyces cerevisiae mediates the anchoring of transcribed genes to the nuclear pore, linking transcription elongation with mRNA export and genome stability, as shown for specific reporters. However, it is still unknown whether the function of TREX-2 is global and the reason for its relevant role in genome integrity. Here, by studying two TREX-2 representative subunits, Thp1 and Sac3, we show that TREX-2 has a genome-wide role in gene expression. Both proteins show similar distributions along the genome, with a gradient disposition at active genes that increases towards the 3' end. Thp1 and Sac3 have a relevant impact on the expression of long, G+C-rich and highly transcribed genes. Interestingly, replication impairment detected by the genome-wide accumulation of the replicative Rrm3 helicase is increased preferentially at highly expressed genes in the thp1 and sac3 mutants analyzed. Therefore, our work provides evidence of a function of TREX-2 at the genome-wide level and suggests a role for TREX-2 in preventing transcription–replication conflicts, as a source of genome instability derived from a defective messenger ribonucleoprotein particle (mRNP) biogenesis.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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