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      Advances in mechanisms of genetic instability related to hereditary neurological diseases

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          Abstract

          Substantial progress has been realized in the past several years in our understanding of the molecular mechanisms responsible for the expansions and deletions (genetic instabilities) of repeating tri-, tetra- and pentanucleotide repeating sequences associated with a number of hereditary neurological diseases. These instabilities occur by replication, recombination and repair processes, probably acting in concert, due to slippage of the DNA complementary strands relative to each other. The biophysical properties of the folded-back repeating sequence strands play a critical role in these instabilities. Non-B DNA structural elements (hairpins and slipped structures, DNA unwinding elements, tetraplexes, triplexes and sticky DNA) are described. The replication mechanisms are influenced by pausing of the replication fork, orientation of the repeat strands, location of the repeat sequences relative to replication origins and the flap endonuclease. Methyl-directed mismatch repair, nucleotide excision repair, and repair of damage caused by mutagens are discussed. Genetic recombination and double-strand break repair advances in Escherichia coli, yeast and mammalian models are reviewed. Furthermore, the newly discovered capacities of certain triplet repeat sequences to cause gross chromosomal rearrangements are discussed.

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          Most cited references169

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          Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

          C Liquori (2001)
          Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.
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            Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function.

            Loss of fragile X mental retardation protein (FMRP) function causes the fragile X mental retardation syndrome. FMRP harbors three RNA binding domains, associates with polysomes, and is thought to regulate mRNA translation and/or localization, but the RNAs to which it binds are unknown. We have used RNA selection to demonstrate that the FMRP RGG box binds intramolecular G quartets. This data allowed us to identify mRNAs encoding proteins involved in synaptic or developmental neurobiology that harbor FMRP binding elements. The majority of these mRNAs have an altered polysome association in fragile X patient cells. These data demonstrate that G quartets serve as physiologically relevant targets for FMRP and identify mRNAs whose dysregulation may underlie human mental retardation.
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              Mismatch repair in replication fidelity, genetic recombination, and cancer biology.

              Mismatch repair stabilizes the cellular genome by correcting DNA replication errors and by blocking recombination events between divergent DNA sequences. The reaction responsible for strand-specific correction of mispaired bases has been highly conserved during evolution, and homologs of bacterial MutS and MutL, which play key roles in mismatch recognition and initiation of repair, have been identified in yeast and mammalian cells. Inactivation of genes encoding these activities results in a large increase in spontaneous mutability, and in the case of mice and men, predisposition to tumor development.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Research
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                2005
                2005
                8 July 2005
                : 33
                : 12
                : 3785-3798
                Affiliations
                Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Texas Medical Center 2121 W. Holcombe Blvd. Houston, TX 77030, USA
                Author notes
                *To whom correspondence should be addressed. Tel: +1 713 677 7651; Fax: +1 713 677 7689; Email: rwells@ 123456ibt.tamhsc.edu
                Article
                10.1093/nar/gki697
                1174910
                16006624
                b8e57bf3-87e2-4566-8568-03af9e63974c
                © The Author 2005. Published by Oxford University Press. All rights reserved

                The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@ 123456oupjournals.org

                History
                : 20 April 2005
                : 09 June 2005
                : 20 June 2005
                Categories
                Survey and Summary

                Genetics
                Genetics

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