Article

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: 8.17). 01/2010; 6(1):e1000810. DOI: 10.1371/journal.pgen.1000810
Source: PubMed

ABSTRACT 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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    • "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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    • "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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    • "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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