title: Genome instability and transcription elongation impairment in human cells depleted of THO/TREX.
abstract: THO/TREX connects transcription with genome integrity in yeast, but a role of mammalian THO in these processes is uncertain, which suggests a differential implication of mRNP biogenesis factors in genome integrity in yeast and humans. We show that human THO depletion impairs transcription elongation and mRNA export and increases instability associated with DNA breaks, leading to hyper-recombination and γH2AX and 53BP1 foci accumulation. This is accompanied by replication alteration as determined by DNA combing. Genome instability is R-loop-dependent, as deduced from the ability of the AID enzyme to increase DNA damage and of RNaseH to reduce it, or from the enhancement of R-loop-dependent class-switching caused by THOC1-depletion in CH12 murine cells. Therefore, mammalian THO prevents R-loop formation and has a role in genome dynamics and function consistent with an evolutionary conservation of the functional connection between these mRNP biogenesis factors and genome integrity that had not been anticipated.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Domínguez-Sánchez
authors.forename: Sonia
authors.initials: S
authors.lastname: Barroso
authors.forename: Belén
authors.initials: B
authors.lastname: Gómez-González
authors.forename: Rosa
authors.initials: R
authors.lastname: Luna
authors.forename: Andrés
authors.initials: A
authors.lastname: Aguilera
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins; D005090:Exodeoxyribonucleases / Q000235:genetics*; D020868:Gene Silencing; D042822:Genomic Instability / Q000235:genetics*; D006367:HeLa Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D011995:Recombination, Genetic / Q000235:genetics*; D016914:Ribonuclease H / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D000071857:Tumor Suppressor p53-Binding Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C400546:THOC1 protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C026452:messenger ribonucleoprotein; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D016914:Ribonuclease H; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase