Co-Orientation of Replication and Transcription Preserves Genome Integrity

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
PLoS Genetics (Impact Factor: 7.53). 01/2010; 6(1):e1000810. DOI: 10.1371/journal.pgen.1000810
Source: PubMed


In many bacteria, there is a genome-wide bias towards co-orientation of replication and transcription, with essential and/or highly-expressed genes further enriched co-directionally. We previously found that reversing this bias in the bacterium Bacillus subtilis slows replication elongation, and we proposed that this effect contributes to the evolutionary pressure selecting the transcription-replication co-orientation bias. This selection might have been based purely on selection for speedy replication; alternatively, the slowed replication might actually represent an average of individual replication-disruption events, each of which is counter-selected independently because genome integrity is selected. To differentiate these possibilities and define the precise forces driving this aspect of genome organization, we generated new strains with inversions either over approximately 1/4 of the chromosome or at ribosomal RNA (rRNA) operons. Applying mathematical analysis to genomic microarray snapshots, we found that replication rates vary dramatically within the inverted genome. Replication is moderately impeded throughout the inverted region, which results in a small but significant competitive disadvantage in minimal medium. Importantly, replication is strongly obstructed at inverted rRNA loci in rich medium. This obstruction results in disruption of DNA replication, activation of DNA damage responses, loss of genome integrity, and cell death. Our results strongly suggest that preservation of genome integrity drives the evolution of co-orientation of replication and transcription, a conserved feature of genome organization.

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Available from: Jue D Wang, Oct 05, 2015
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    • "It can result in specific patterns of localization or orientation of genes in the chromosome GBE relative to the origin or replication and the direction of advance of the replication fork. For example, highly expressed genes tend to cluster near the origin of replication in fastreplicating bacteria (Couturier and Rocha 2006), and essential operons like those encoding the highly expressed rrn genes tend to be placed in the leading strand, possibly to prevent the instability caused by head-on clashes between the replication and transcription machineries (Rocha and Danchin 2003; Srivatsan et al. 2010; Paul et al. 2013). ISs are a special class of genetic elements because they could potentially be placed almost anywhere in the chromosome and in any orientation. "
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    ABSTRACT: Insertion Sequences (ISs) are small transposable elements widespread in bacterial genomes, where they play an essential role in chromosome evolution by stimulating recombination and genetic flow. Despite their ubiquity, it is unclear how ISs interact with the host. Here we report a survey of the orientation patterns of ISs in bacterial chromosomes with the objective of gaining insight into the interplay between ISs and host chromosomal functions. We find that a significant fraction of IS families present a consistent and family-specific orientation bias with respect to chromosomal DNA replication, especially in Firmicutes. Additionally, we find that the transposases of up to 9 different IS families with different transposition pathways interact with the β sliding clamp, an essential replication factor, suggesting that this is a widespread mechanism of interaction with the host. While we find evidence that the interaction with the β sliding clamp is common to all bacterial phyla, it also could explain the observed strong orientation bias found in Firmicutes, since in this group β is asymmetrically distributed during synthesis of the leading or lagging strands. Besides the interaction with the β sliding clamp, other asymmetries also play a role in the biased orientation of some IS families. The utilization of the highly conserved replication sliding clamps suggests a mechanism for host regulation of IS proliferation and also a universal platform for IS dispersal and transmission within bacterial populations and among phyllogenetically distant species.
    Genome Biology and Evolution 03/2014; 6(3). DOI:10.1093/gbe/evu052 · 4.23 Impact Factor
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    • "Replication is the most vulnerable period of the cell cycle to accumulate genomic instability and DNA damage [11]: deletion of the earliest origin on yeast chromosome VI increased the mutation rate by 30% [23], while the frequency of intergenic mutations was significantly higher in late DNA replication regions in human cancer genomes [26]. In bacteria, coorientation of replication and transcription has been linked to a selection for speedy replication, as slower replication imposed a small but significant competitive disadvantage [46]. "
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    ABSTRACT: Nothing is more fundamental to life than the ability to reproduce and duplicate the information cells store in their genomes. The mechanism of duplication of DNA has been conserved from prokaryotes to eukaryotes. The aim of the study was to quantify which evolution-ary forces could produce the pattern of genome replication architecture observed in present-day organisms. This was achieved using an evolutionary simulation, combining random genome sequence shuffling, mutation, selection and the mathematical modeling of DNA replication. We have found parameter values which explained evolutionary pressures of DNA replication in E.coli, P.calidifontis and S. cerevisae. Surprisingly, the results of the evolutionary simulation suggests that for a fixed cost per replication origin it is more advantageous for genomes to reduce the number of replication origins under increasing uncertainty in origin activation timing.
    Mathematical Modelling of Natural Phenomena 01/2014; 9(3):96-106. DOI:10.1051/mmnp/20149306 · 0.81 Impact Factor
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    • "The large number of strategies that prokaryotic and eukaryotic organisms have developed to minimize collisions between transcription and replication highlights the relevance of coordinating genomic trafficking to preserve genomic integrity. However, clashes between transcription and replication machineries still occur in eukaryotic cells, for instance, when transcription occurs in replicating cells, having relevant implications for cancer, or when there is an outburst of transcription during S phase [10] [60]. "
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    ABSTRACT: Transcription during Sphase needs to be spatially and temporally regulated to prevent collisions between the transcription and replication machineries. Cells have evolved a number of mechanisms to make compatible both processes under normal growth conditions. When conflict management fails, the head-on encounter between RNA and DNA polymerases results in genomic instability unless conflict resolution mechanisms are activated. Nevertheless, there are specific situations in which cells need to dramatically change their transcriptional landscape to adapt to environmental challenges. Signal transduction pathways, such as stress-activated protein kinases (SAPKs), serve to regulate gene expression in response to environmental insults. Prototypical members of SAPKs are the yeast Hog1 and mammalian p38. In response to stress, p38/Hog1 SAPKs control transcription and also regulate cell cycle progression. When yeast cells are stressed during S phase, Hog1 promotes gene induction and remarkably, also delays replication by directly affecting early origin firing and fork progression. Therefore, by delaying replication, Hog1 plays a key role in preventing conflicts between RNA and DNA polymerases. In this review, we focus on the genomic determinants and mechanisms that make compatible transcription with replication during S phase to prevent genomic instability, especially in response to environmental changes.
    Journal of Molecular Biology 09/2013; 425(23). DOI:10.1016/j.jmb.2013.08.019 · 4.33 Impact Factor
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