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

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

Larsson Omberg1,5, Joel R Meyerson1,6, Kayta Kobayashi2,7, Lucy S Drury3, John FX Diffley3,* and Orly Alter1,4,*

1 Department of Biomedical Engineering, University of Texas, Austin, TX, USA,

2 College of Pharmacy, University of Texas, Austin, TX, USA,

3 Cancer Research UK LondonResearch Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, UK and

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

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

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

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

* Corresponding authors. O Alter, Department of Biomedical Engineering and Institutes for Cellular and Molecular Biology and Computational Engineering and Sciences,
University of Texas, Austin, TX 78712, USA. Tel.: þ1 512 471 7939; Fax: þ1 512 471 2149; E-mail: orlyal@mail.utexas.edu and JFX Diffley, Cancer Research UK London
Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK. Tel.: þ44 1707 625 869; Fax: þ44 1707 625 801; E-mail: john.diffley@cancer.org.uk

Received 4.3.09; accepted 19.8.09

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, B88% 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 DNAdamage checkpoint responses. Third, origin licensing decreases the expression of genes with origins near their 30 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.

Molecular Systems Biology 5: 312; published online 13 October 2009; doi:10.1038/msb.2009.70

Subject Categories: functional genomics; cell cycle

Keywords: a higher-order singular value decomposition (HOSVD); cell cycle; DNA replication origin licensing and firing; DNA microarrays; mRNA expression

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