Efeitos globais da replicação de DNA e a atividade de origem de replicação do DNA em expressão de gene eucariótico

Molecular Systems Biology 5 Article number: 312 doi:10.1038/msb.2009.70
Published online: 13 October 2009
Citation: Molecular Systems Biology 5:312

Global effects of DNA replication and DNA replication origin activity on eukaryotic gene expression

Larsson Omberg 1,a, Joel R Meyerson 1,b, Kayta Kobayashi 2,c, Lucy S Drury 3, John F X Diffley 3 & Orly Alter 1,4

Department of Biomedical Engineering, University of Texas, Austin, TX, USA
College of Pharmacy, University of Texas, Austin, TX, USA

Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, UK

Institutes for Cellular and Molecular Biology, and Computational Engineering and Sciences, University of Texas, Austin, TX, USA

Correspondence to: Orly Alter1,4 Department of Biomedical Engineering and Institutes for Cellular and Molecular Biology and Computational Engineering and Sciences, University of Texas, Austin, TX 78712, USA. Tel.: +1 512 471 7939; Fax: +1 512 471 2149; Email: orlyal@mail.utexas.edu

Correspondence to: John F X Diffley3 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK. Tel.: +44 1707 625 869; Fax: +44 1707 625 801; Email: john.diffley@cancer.org.uk

Received 4 March 2009; Accepted 19 August 2009; Published online 13 October 2009

This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits distribution and reproduction in any medium, provided the original author and source are credited. Creation of derivative works is permitted but the resulting work may be distributed only under the same or similar licence to this one. This licence does not permit commercial exploitation without specific permission.

aPresent address: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA

bPresent address: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

cPresent address: Pharmacy Department, Intermountain Medical Center, Murray, UT 84157, USA

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Abstract

This report provides a global view of how gene expression is affected by DNA replication. We analyzed synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression. We use a higher-order singular value decomposition to integrate the global mRNA expression measured in the multiple time courses, detect and remove experimental artifacts and identify significant combinations of patterns of expression variation across the genes, time points and conditions. We find that, first, 88% of the global mRNA expression is independent of DNA replication. Second, the requirement of DNA replication for efficient histone gene expression is independent of conditions that elicit DNA damage checkpoint responses. Third, origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes. This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression, and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

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