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      G-quadruplexes and helicases

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          Abstract

          Guanine-rich DNA strands can fold in vitro into non-canonical DNA structures called G-quadruplexes. These structures may be very stable under physiological conditions. Evidence suggests that G-quadruplex structures may act as ‘knots’ within genomic DNA, and it has been hypothesized that proteins may have evolved to remove these structures. The first indication of how G-quadruplex structures could be unfolded enzymatically came in the late 1990s with reports that some well-known duplex DNA helicases resolved these structures in vitro. Since then, the number of studies reporting G-quadruplex DNA unfolding by helicase enzymes has rapidly increased. The present review aims to present a general overview of the helicase/G-quadruplex field.

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          Structure and mechanism of helicases and nucleic acid translocases.

          Helicases and translocases are a ubiquitous, highly diverse group of proteins that perform an extraordinary variety of functions in cells. Consequently, this review sets out to define a nomenclature for these enzymes based on current knowledge of sequence, structure, and mechanism. Using previous definitions of helicase families as a basis, we delineate six superfamilies of enzymes, with examples of crystal structures where available, and discuss these structures in the context of biochemical data to outline our present understanding of helicase and translocase activity. As a result, each superfamily is subdivided, where appropriate, on the basis of mechanistic understanding, which we hope will provide a framework for classification of new superfamily members as they are discovered and characterized.
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            The Bloom's syndrome gene product is homologous to RecQ helicases.

            The Bloom's syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.
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              DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase.

              G-quadruplex (G4) DNA structures are extremely stable four-stranded secondary structures held together by noncanonical G-G base pairs. Genome-wide chromatin immunoprecipitation was used to determine the in vivo binding sites of the multifunctional Saccharomyces cerevisiae Pif1 DNA helicase, a potent unwinder of G4 structures in vitro. G4 motifs were a significant subset of the high-confidence Pif1-binding sites. Replication slowed in the vicinity of these motifs, and they were prone to breakage in Pif1-deficient cells, whereas non-G4 Pif1-binding sites did not show this behavior. Introducing many copies of G4 motifs caused slow growth in replication-stressed Pif1-deficient cells, which was relieved by spontaneous mutations that eliminated their ability to form G4 structures, bind Pif1, slow DNA replication, and stimulate DNA breakage. These data suggest that G4 structures form in vivo and that they are resolved by Pif1 to prevent replication fork stalling and DNA breakage. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                18 March 2016
                15 February 2016
                15 February 2016
                : 44
                : 5
                : 1989-2006
                Affiliations
                [1 ]University of Bordeaux, ARNA Laboratory F-33000 Bordeaux, France
                [2 ]INSERM U1212,CNRS UMR 5320, IECB, F-33600 Pessac, France
                [3 ]CNRS UMR 7196, INSERM U1154, MNHN, F-75005 Paris, France
                [4 ]Sorbonne Universités, F-75005 Paris, France
                [5 ]Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +33 5 4000 3022; Email: jean-louis.mergny@ 123456inserm.fr
                Correspondence may also be addressed to Jean-Baptiste Boulé. Tel: +33 1 40 79 56 16; Email: jean-baptiste.boule@ 123456mnhn.fr
                Correspondence may also be addressed to Robert M. Brosh Jr. Tel: +1 410 558 8578; Email: broshr@ 123456grc.nia.nih.gov
                Article
                10.1093/nar/gkw079
                4797304
                26883636
                768df57a-0354-4d79-b3a3-a2fb2a7b2b47
                © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 01 February 2016
                : 26 January 2016
                : 24 November 2015
                Page count
                Pages: 18
                Categories
                Survey and Summary
                Custom metadata
                18 March 2016

                Genetics
                Genetics

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