Human gene organization driven by the coordination of replication and transcription.

Centre de Génétique Moléculaire (CNRS), 91198 Gif-sur-Yvette, France.
Genome Research (Impact Factor: 14.4). 10/2007; 17(9):1278-85. DOI: 10.1101/gr.6533407
Source: PubMed

ABSTRACT In this work, we investigated a large-scale organization of the human genes with respect to putative replication origins. We developed an appropriate multiscale method to analyze the nucleotide compositional skew along the genome and found that in more than one-quarter of the genome, the skew profile presents characteristic patterns consisting of successions of N-shaped structures, designated here N-domains, bordered by putative replication origins. Our analysis of recent experimental timing data confirmed that, in a number of cases, domain borders coincide with replication initiation zones active in the early S phase, whereas the central regions replicate in the late S phase. Around the putative origins, genes are abundant and broadly expressed, and their transcription is co-oriented with replication fork progression. These features weaken progressively with the distance from putative replication origins. At the center of domains, genes are rare and expressed in few tissues. We propose that this specific organization could result from the constraints of accommodating the replication and transcription initiation processes at chromatin level, and reducing head-on collisions between the two machineries. Our findings provide a new model of gene organization in the human genome, which integrates transcription, replication, and chromatin structure as coordinated determinants of genome architecture.

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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; · 3.91 Impact Factor
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    ABSTRACT: DNA damage leads to heritable changes in the genome via DNA replication. However, as the DNA helix is the site of numerous other transactions, notably transcription, DNA damage can have diverse repercussions on cellular physiology. In particular, DNA lesions have distinct effects on the passage of transcribing RNA polymerases, from easy bypass to almost complete block of transcription elongation. The fate of the RNA polymerase positioned at a lesion is largely determined by whether the lesion is structurally subtle and can be accommodated and eventually bypassed, or bulky, structurally distorting and requiring remodeling/complete dissociation of the transcription elongation complex, excision, and repair. Here we review cellular responses to DNA damage that involve RNA polymerases with a focus on bacterial transcription-coupled nucleotide excision repair and lesion bypass via transcriptional mutagenesis. Emphasis is placed on the explosion of new structural information on RNA polymerases and relevant DNA repair factors and the mechanistic models derived from it.
    Cellular and Molecular Life Sciences CMLS 06/2013; · 5.62 Impact Factor
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    08/2011; , ISBN: 978-953-307-593-8

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