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      G4 motifs correlate with promoter-proximal transcriptional pausing in human genes

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          Abstract

          The RNA Pol II transcription complex pauses just downstream of the promoter in a significant fraction of human genes. The local features of genomic structure that contribute to pausing have not been defined. Here, we show that genes that pause are more G-rich within the region flanking the transcription start site (TSS) than RefSeq genes or non-paused genes. We show that enrichment of binding motifs for common transcription factors, such as SP1, may account for G-richness upstream but not downstream of the TSS. We further show that pausing correlates with the presence of a GrIn1 element, an element bearing one or more G4 motifs at the 5′-end of the first intron, on the non-template DNA strand. These results suggest potential roles for dynamic G4 DNA and G4 RNA structures in cis-regulation of pausing, and thus genome-wide regulation of gene expression, in human cells.

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          Most cited references 37

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          The NCI60 human tumour cell line anticancer drug screen.

          The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.
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            A gene expression database for the molecular pharmacology of cancer.

            We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discovery screen by the National Cancer Institute. Using these data, we linked bioinformatics and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very different from those obtained by clustering the cell lines on the basis of their response to drugs. Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance. This is the first study to integrate large databases on gene expression and molecular pharmacology.
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              Gene function correlates with potential for G4 DNA formation in the human genome

              G-rich genomic regions can form G4 DNA upon transcription or replication. We have quantified the potential for G4 DNA formation (G4P) of the 16 654 genes in the human RefSeq database, and then correlated gene function with G4P. We have found that very low and very high G4P correlates with specific functional classes of genes. Notably, tumor suppressor genes have very low G4P and proto-oncogenes have very high G4P. G4P of these genes is evenly distributed between exons and introns, and it does not reflect enrichment for CpG islands or local chromosomal environment. These results show that genomic structure undergoes selection based on gene function. Selection based on G4P could promote genomic stability (or instability) of specific classes of genes; or reflect mechanisms for global regulation of gene expression.
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                Author and article information

                Journal
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                July 2011
                July 2011
                3 March 2011
                3 March 2011
                : 39
                : 12
                : 4975-4983
                Affiliations
                1Molecular and Cellular Biology Graduate Program, 2Department of Immunology, 3Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, 4Lombardi Comprehensive Cancer Center, Georgetown University Medical Center and 5Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195-7650, USA
                Author notes
                *To whom correspondence should be addressed. Tel: +206 221 6876; Fax: +206 221 6781; Email: maizels@ 123456u.washington.edu
                Reprint Requests to Nancy Maizels, Department of Immunology and Department of Biochemistry, University of Washington School of Medicine, Box 357650, Seattle, WA 98195-7650. Tel: +206 221 6876; Fax: +206 221 6781; Email: maizels@ 123456u.washington.edu

                This article is dedicated to the memory of Johanna Eddy who passed away soon after receiving her PhD degree, following a courageous struggle with breast cancer. Her creativity and eagerness to rise to every challenge will continue to inspire everyone lucky enough to have worked with her.

                Article
                gkr079
                10.1093/nar/gkr079
                3130262
                21371997
                59ed971b-a354-4396-9184-e35f9a41149a
                © The Author(s) 2011. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 9
                Categories
                Gene Regulation, Chromatin and Epigenetics

                Genetics

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