Co-orientation of replication and transcription preserves genome integrity.

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2010-01-15

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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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10.1371/journal.pgen.1000810

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Srivatsan, Anjana, Ashley Tehranchi, David M MacAlpine and Jue D Wang (2010). Co-orientation of replication and transcription preserves genome integrity. PLoS Genet, 6(1). p. e1000810. 10.1371/journal.pgen.1000810 Retrieved from https://hdl.handle.net/10161/4458.

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Scholars@Duke

MacAlpine

David MacAlpine

Professor of Pharmacology and Cancer Biology

Our laboratory is interested in understanding the mechanisms by which the molecular architecture of the chromosome regulates fundamental biological processes such as replication and transcription. Specifically, how are replication, transcription and chromatin modification coordinated on a genomic scale to maintain genomic stability? We are addressing this question by using genomic, computational and biochemical approaches in the model organism Drosophila melanogaster.

DNA replication is an essential cell cycle event required for the timely and accurate duplication of chromosomes. Replication initiates at multiple sites (called origins of replication) distributed across each chromosome. The failure to properly regulate origin selection and activation may result in catastrophic genomic instability and potentially tumorigenesis. Recent metazoan genomic studies have demonstrated a correlation between time of DNA replication and transcriptional activity, with actively transcribed regions of the genome being replicated early. However, the underlying mechanism of this correlation remains unclear. By systematically characterizing the replication dynamics of multiple cell types, each with distinct transcriptional programs, we will be in a position to understand how these processes are coordinated.

Another goal of the laboratory is to identify the chromosomal features that direct and regulate metazoan DNA replication. Origins of DNA replication are marked by the formation of multi-protein complex, called the preRC. Despite conservation of the proteins that comprise the preRC in all eukaryotes, very little is known about the sequence elements required for the selection and regulation of metazoan origins. We are using genomic tiling microarrays to systematically map all the sites of preRC assembly in the Drosophila genome. The high resolution mapping of thousands of replication origins will provide an unprecedented opportunity to use both computational approaches and comparative genomics to identify cis-acting elements that may regulate replication.


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