Document Detail


Genome-wide screen identifies pathways that govern GAA/TTC repeat fragility and expansions in dividing and nondividing yeast cells.
MedLine Citation:
PMID:  22959270     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Triplex structure-forming GAA/TTC repeats pose a dual threat to the eukaryotic genome integrity. Their potential to expand can lead to gene inactivation, the cause of Friedreich's ataxia disease in humans. In model systems, long GAA/TTC tracts also act as chromosomal fragile sites that can trigger gross chromosomal rearrangements. The mechanisms that regulate the metabolism of GAA/TTC repeats are poorly understood. We have developed an experimental system in the yeast Saccharomyces cerevisiae that allows us to systematically identify genes crucial for maintaining the repeat stability. Two major groups of mutants defective in DNA replication or transcription initiation are found to be prone to fragility and large-scale expansions. We demonstrate that problems imposed by the repeats during DNA replication in actively dividing cells and during transcription initiation in nondividing cells can culminate in genome instability. We propose that similar mechanisms can mediate detrimental metabolism of GAA/TTC tracts in human cells.
Authors:
Yu Zhang; Alexander A Shishkin; Yuri Nishida; Dana Marcinkowski-Desmond; Natalie Saini; Kirill V Volkov; Sergei M Mirkin; Kirill S Lobachev
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-09-06
Journal Detail:
Title:  Molecular cell     Volume:  48     ISSN:  1097-4164     ISO Abbreviation:  Mol. Cell     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-29     Completed Date:  2013-04-03     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  9802571     Medline TA:  Mol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  254-65     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
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MeSH Terms
Descriptor/Qualifier:
Chromosome Fragility / genetics*
DNA Replication
Friedreich Ataxia / genetics*
Genome, Fungal
Genome, Human
Genomic Instability
Humans
Microsatellite Repeats
Mutation
Nucleic Acid Conformation
Saccharomyces cerevisiae / genetics*
Trinucleotide Repeats / genetics*
Grant Support
ID/Acronym/Agency:
R01 GM060987/GM/NIGMS NIH HHS; R01GM0825950/GM/NIGMS NIH HHS; R01GM60987/GM/NIGMS NIH HHS
Comments/Corrections

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