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• W2743251723 abstract "Interference between DNA replication and transcription represents a major source of genomic instability. In this issue of Cell, Lang et al. and Hamperl et al. show that head-on collisions, but not codirectional collisions, impede fork progression in bacteria and in human cells by promoting the formation of RNA-DNA hybrids known as R-loops. Interference between DNA replication and transcription represents a major source of genomic instability. In this issue of Cell, Lang et al. and Hamperl et al. show that head-on collisions, but not codirectional collisions, impede fork progression in bacteria and in human cells by promoting the formation of RNA-DNA hybrids known as R-loops. Transcription-replication conflicts (TRCs) represent a major source of spontaneous genomic instability, both in eukaryotes and prokaryotes (García-Muse and Aguilera, 2016García-Muse T. Aguilera A. Nat. Rev. Mol. Cell Biol. 2016; 17: 553-563Crossref PubMed Scopus (210) Google Scholar, Hamperl and Cimprich, 2016Hamperl S. Cimprich K.A. Cell. 2016; 167: 1455-1467Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, Merrikh, 2017Merrikh H. Trends Microbiol. 2017; 25: 515-521Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Indeed, DNA and RNA polymerases operate on the same DNA template and unavoidably interfere with each other. However, the mechanisms involved in this interference remain poorly understood. TRCs may occur in a head-on or co-directional fashion, depending on the orientation of genes relative to the direction of fork progression. In bacteria, most of the genes are organized co-directionally with forks to avoid the more deleterious head-on collisions (Merrikh, 2017Merrikh H. Trends Microbiol. 2017; 25: 515-521Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar), and this bias was also observed in the human genome (Huvet et al., 2007Huvet M. Nicolay S. Touchon M. Audit B. d’Aubenton-Carafa Y. Arneodo A. Thermes C. Genome Res. 2007; 17: 1278-1285Crossref PubMed Scopus (121) Google Scholar, Petryk et al., 2016Petryk N. Kahli M. d’Aubenton-Carafa Y. Jaszczyszyn Y. Shen Y. Silvain M. Thermes C. Chen C.-L. Hyrien O. Nat. Commun. 2016; 7: 10208Crossref PubMed Scopus (165) Google Scholar). Alternatively, TRCs could be caused by co-transcriptional R-loops, which interfere with replication, leading to fork collapse and chromosome rearrangements (García-Muse and Aguilera, 2016García-Muse T. Aguilera A. Nat. Rev. Mol. Cell Biol. 2016; 17: 553-563Crossref PubMed Scopus (210) Google Scholar). These structures are formed at specific sites when the nascent transcript reanneals with the template DNA behind the RNA polymerase, leaving the non-coding strand unpaired (Figure 1). Whether R-loops represent a cause or a consequence of head-on collisions is currently unknown. In this issue of Cell, two articles from the Cimprich and Merrikh laboratories reveal that replication forks approaching highly transcribed genes in a head-on orientation, but not in a co-directional orientation, induce the formation of R-loops and promote TRCs, both in the bacterium Bacillus subtilis and in human cells (Lang et al., 2017Lang K.S. Hall A.N. Merrikh C.N. Ragheb M. Tabakh H. Pollock A.J. Woodward J.J. Dreifus J.E. Merrikh H. Cell. 2017; 170 (this issue): 787-799Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, Hamperl et al., 2017Hamperl S. Bocek M.J. Saldivar J.C. Swigut T. Cimprich K.A. Cell. 2017; 170 (this issue): 774-786Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). These findings have major implications for the stability and the evolution of complex genomes under stress conditions. The impact of gene orientation on TRCs has been the subject of intense research for several decades. Pioneering studies in budding yeast have shown that head-on conflicts lead to transcription-associated recombination (Prado and Aguilera, 2005Prado F. Aguilera A. EMBO J. 2005; 24: 1267-1276Crossref PubMed Scopus (213) Google Scholar) and that R-loops contribute to fork arrest in different species, from bacteria to human (Hamperl and Cimprich, 2016Hamperl S. Cimprich K.A. Cell. 2016; 167: 1455-1467Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, Wellinger et al., 2006Wellinger R.E. Prado F. Aguilera A. Mol. Cell. Biol. 2006; 26: 3327-3334Crossref PubMed Scopus (123) Google Scholar). Since the overexpression of RNase H suppresses TRCs by degrading RNA-DNA hybrids, it is generally believed that R-loops interfere with fork progression, regardless of the orientation of genes or the presence of RNA polymerases (García-Muse and Aguilera, 2016García-Muse T. Aguilera A. Nat. Rev. Mol. Cell Biol. 2016; 17: 553-563Crossref PubMed Scopus (210) Google Scholar). However, the mechanism by which gene orientation impacts fork collision and/or R-loop formation has never been directly investigated. Addressing this question is particularly challenging in the context of the human genome because of the low efficiency and plasticity of replication origins and the fact that most genes are replicated from both directions in a cell population (Petryk et al., 2016Petryk N. Kahli M. d’Aubenton-Carafa Y. Jaszczyszyn Y. Shen Y. Silvain M. Thermes C. Chen C.-L. Hyrien O. Nat. Commun. 2016; 7: 10208Crossref PubMed Scopus (165) Google Scholar). Moreover, RNase H is involved in multiple biological processes, and its overexpression could affect TRCs independently of R-loop homeostasis. To circumvent these problems, Hamperl et al., 2017Hamperl S. Bocek M.J. Saldivar J.C. Swigut T. Cimprich K.A. Cell. 2017; 170 (this issue): 774-786Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar designed an original episomal system containing a unidirectional replication origin next to an inducible reporter gene in a head-on or co-directional orientation. Importantly, two reporter genes were used to monitor the contribution of R-loops without overexpressing RNase H: one prone to RNA-DNA hybrid formation and another that did not form hybrids. They find that head-on conflicts increase plasmid instability in human cells and induced a checkpoint response, but only in the presence of R-loops. Remarkably, they also found that head-on collisions increase R-loop formation, whereas co-directional collisions favor the clearance of R-loops. To determine whether this also applies to chromosomal loci, Hamperl et al., 2017Hamperl S. Bocek M.J. Saldivar J.C. Swigut T. Cimprich K.A. Cell. 2017; 170 (this issue): 774-786Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar monitored the distribution of R-loops genome-wide by DNA-RNA hybrid immunoprecipitation and next-generation sequencing (DRIP-seq). This analysis reveals that R-loops form preferentially, where replication forks and transcription are oriented head-on compared to genomic regions, where they are codirectionally oriented. These data suggest that the co-orientation bias of the human genome (Petryk et al., 2016Petryk N. Kahli M. d’Aubenton-Carafa Y. Jaszczyszyn Y. Shen Y. Silvain M. Thermes C. Chen C.-L. Hyrien O. Nat. Commun. 2016; 7: 10208Crossref PubMed Scopus (165) Google Scholar) may help to minimize the accumulation of deleterious R-loops. This finding is important because it provides a mechanistic basis for increased R-loops in cells depleted for factors involved in fork stability, such as BRCA1 and BRCA2 (García-Muse and Aguilera, 2016García-Muse T. Aguilera A. Nat. Rev. Mol. Cell Biol. 2016; 17: 553-563Crossref PubMed Scopus (210) Google Scholar). Hamperl et al., 2017Hamperl S. Bocek M.J. Saldivar J.C. Swigut T. Cimprich K.A. Cell. 2017; 170 (this issue): 774-786Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar also report that R-loops induce DNA damage, checkpoint activation, and plasmid degradation in both orientations. This toxicity could reflect the fact that stalled forks cannot be rescued by converging forks on the episome, as would be the case on the chromosome. Further work will tell whether co-directional collisions also induce breaks at chromosomal loci. In a parallel study, Lang et al., 2017Lang K.S. Hall A.N. Merrikh C.N. Ragheb M. Tabakh H. Pollock A.J. Woodward J.J. Dreifus J.E. Merrikh H. Cell. 2017; 170 (this issue): 787-799Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar engineered a conflict system consisting of inducible reporter genes inserted in both orientations on the circular chromosome of Bacillus subtilis. They showed that, as in human cells, head-on-oriented genes are particularly disruptive to DNA replication because they form stable R-loops that block fork progression and prevent restart. This replication-dependent formation of R-loops at head-on genes also blocks transcription. Moreover, replication resumption and cell viability was exquisitely dependent on RNase HIII, but increased mutagenesis in head-on genes. These findings have major implications for the physiology and evolution of bacteria. Indeed, although most genes are organized in a co-directional orientation in bacterial genomes, some key virulence and stress response genes are oriented head-on. It was previously reported that TRCs accelerate the evolution of these genes by inducing specific mutations (Paul et al., 2013Paul S. Million-Weaver S. Chattopadhyay S. Sokurenko E. Merrikh H. Nature. 2013; 495: 512-515Crossref PubMed Scopus (93) Google Scholar). Since R-loops form preferentially at these genes in a replication-dependent manner, and since R-loop clearance is required for both cell viability and accelerated mutagenesis, these data shed new light on the mechanism by which TRC resolution drives the rapid evolution of stress genes. To support this view, Lang et al., 2017Lang K.S. Hall A.N. Merrikh C.N. Ragheb M. Tabakh H. Pollock A.J. Woodward J.J. Dreifus J.E. Merrikh H. Cell. 2017; 170 (this issue): 787-799Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar show that R-loop resolution is required for the efficient replication of pathogenic bacteria in eukaryotic cells and infection of mice. This mechanism should elevate mutagenesis of critical head-on virulence and stress genes during infections, endangering bacterial life while potentially promoting pathogen adaptation. In conclusion, Lang et al., 2017Lang K.S. Hall A.N. Merrikh C.N. Ragheb M. Tabakh H. Pollock A.J. Woodward J.J. Dreifus J.E. Merrikh H. Cell. 2017; 170 (this issue): 787-799Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar report an original mechanism by which the orientation of specific genes on bacterial chromosomes promote directed mutagenesis in a replication-dependent manner through the formation and the resolution of R-loops. Interestingly, this mechanism is very similar to the one described by Hamperl et al., 2017Hamperl S. Bocek M.J. Saldivar J.C. Swigut T. Cimprich K.A. Cell. 2017; 170 (this issue): 774-786Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar in human cells. In these cells, alterations of the DNA replication program increased the formation of R-loops, presumably by increasing the frequency of head-on collisions. Since deregulated oncogene expression in cancer cells potentially alters replication profiles, it is tempting to speculate that TRCs may also play an active role in the evolution of cancer genomes by promoting rearrangements at cancer genes, as it is the case for virulence genes in bacteria. Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage ResponsesHamperl et al.CellAugust 10, 2017In BriefCollisions between transcription and replication complexes activate distinct DNA damage responses depending on whether they meet head-on or are moving in the same direction. Full-Text PDF Open ArchiveReplication-Transcription Conflicts Generate R-Loops that Orchestrate Bacterial Stress Survival and PathogenesisLang et al.CellAugust 10, 2017In BriefHead-on replication-transcription collisions lead to pervasive R-loop formation, which must be resolved for bacterial stress survival and pathogenesis. Full-Text PDF Open Archive" @default.
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• W2743251723 title "Transcription-Replication Conflicts: Orientation Matters" @default.
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