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      Interconverting Conformations of Slipped-DNA Junctions Formed by Trinucleotide Repeats Affect Repair Outcome

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          Abstract

          Expansions of (CTG)·(CAG) repeated DNAs are the mutagenic cause of 14 neurological diseases, likely arising through the formation and processing of slipped-strand DNAs. These transient intermediates of repeat length mutations are formed by out-of-register mispairing of repeat units on complementary strands. The three-way slipped-DNA junction, at which the excess repeats slip out from the duplex, is a poorly understood feature common to these mutagenic intermediates. Here, we reveal that slipped junctions can assume a surprising number of interconverting conformations where the strand opposite the slip-out either is fully base paired or has one or two unpaired nucleotides. These unpaired nucleotides can also arise opposite either of the nonslipped junction arms. Junction conformation can affect binding by various structure-specific DNA repair proteins and can also alter correct nick-directed repair levels. Junctions that have the potential to contain unpaired nucleotides are repaired with a significantly higher efficiency than constrained fully paired junctions. Surprisingly, certain junction conformations are aberrantly repaired to expansion mutations: misdirection of repair to the non-nicked strand opposite the slip-out leads to integration of the excess slipped-out repeats rather than their excision. Thus, slipped-junction structure can determine whether repair attempts lead to correction or expansion mutations.

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          Most cited references56

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          Repeat instability: mechanisms of dynamic mutations.

          Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.
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            Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.

            Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.
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              Repeat instability as the basis for human diseases and as a potential target for therapy.

              Expansions of repetitive DNA sequences cause numerous human neurological and neuromuscular diseases. Ongoing repeat expansions in patients can exacerbate disease progression and severity. As pathogenesis is connected to repeat length, a potential therapeutic avenue is to modulate disease by manipulating repeat expansion size--targeting DNA, the root-cause of symptoms. How repeat instability is mediated by DNA replication, repair, recombination, transcription and epigenetics may explain its contribution to pathogenesis and give insights into therapeutic strategies to block expansions or induce contractions.
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                Author and article information

                Journal
                Biochemistry
                Biochemistry
                bi
                bichaw
                Biochemistry
                American Chemical Society
                0006-2960
                1520-4995
                22 January 2013
                05 February 2013
                : 52
                : 5
                : 773-785
                Affiliations
                []Program of Genetics and Genome Biology, The Hospital for Sick Children , Toronto, ON M5G 1L7, Canada
                []Department of Molecular Genetics, University of Toronto , Toronto, ON M5G 1L7, Canada
                [§ ]Institute of Molecules and Materials, Department of Biophysical Chemistry, Radboud University Nijmegen , Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
                []Department of Pharmacological Sciences and Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States
                Author notes
                [* ]Program of Genetics and Genome Biology, The Hospital for Sick Children, TMDT 15-312, 101 College St., Toronto, ON M5G 1L7, Canada. Telephone: (416) 813-8256. Fax: (416) 813-4931. E-mail: cepearson.sickkids@ 123456gmail.com .
                Article
                10.1021/bi301369b
                3566650
                23339280
                d2153c70-2442-4148-b345-c1e70d6a79e1
                Copyright © 2013 American Chemical Society

                This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.

                History
                : 05 October 2012
                : 08 December 2012
                Funding
                National Institutes of Health, United States
                Categories
                Article
                Custom metadata
                bi301369b
                bi-2012-01369b

                Biochemistry
                Biochemistry

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