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    Replication Stalling and Heteroduplex Formation within CAG/CTG Trinucleotide Repeats by Mismatch Repair

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    Type
    Article
    Authors
    Viterbo, David
    Michoud, Gregoire cc
    Mosbach, Valentine
    Dujon, Bernard
    Richard, Guy-Franck
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2016-03-16
    Online Publication Date
    2016-03-16
    Print Publication Date
    2016-06
    Permanent link to this record
    http://hdl.handle.net/10754/602087
    
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    Abstract
    Trinucleotide repeat expansions are responsible for at least two dozen neurological disorders. Mechanisms leading to these large expansions of repeated DNA are still poorly understood. It was proposed that transient stalling of the replication fork by the repeat tract might trigger slippage of the newly-synthesized strand over its template, leading to expansions or contractions of the triplet repeat. However, such mechanism was never formally proven. Here we show that replication fork pausing and CAG/CTG trinucleotide repeat instability are not linked, stable and unstable repeats exhibiting the same propensity to stall replication forks when integrated in a yeast natural chromosome. We found that replication fork stalling was dependent on the integrity of the mismatch-repair system, especially the Msh2p-Msh6p complex, suggesting that direct interaction of MMR proteins with secondary structures formed by trinucleotide repeats in vivo, triggers replication fork pauses. We also show by chromatin immunoprecipitation that Msh2p is enriched at trinucleotide repeat tracts, in both stable and unstable orientations, this enrichment being dependent on MSH3 and MSH6. Finally, we show that overexpressing MSH2 favors the formation of heteroduplex regions, leading to an increase in contractions and expansions of CAG/CTG repeat tracts during replication, these heteroduplexes being dependent on both MSH3 and MSH6. These heteroduplex regions were not detected when a mutant msh2-E768A gene in which the ATPase domain was mutated was overexpressed. Our results unravel two new roles for mismatch-repair proteins: stabilization of heteroduplex regions and transient blocking of replication forks passing through such repeats. Both roles may involve direct interactions between MMR proteins and secondary structures formed by trinucleotide repeat tracts, although indirect interactions may not be formally excluded.
    Citation
    Replication Stalling and Heteroduplex Formation within CAG/CTG Trinucleotide Repeats by Mismatch Repair 2016 DNA Repair
    Sponsors
    G.-F. R. thanks C. Saveanu and F. Feuerbach for the use of the TAP-tag library and advices on ChIP.
    Publisher
    Elsevier BV
    Journal
    DNA Repair
    DOI
    10.1016/j.dnarep.2016.03.002
    PubMed ID
    27045900
    Additional Links
    http://linkinghub.elsevier.com/retrieve/pii/S156878641530104X
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.dnarep.2016.03.002
    Scopus Count
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    Articles; Biological and Environmental Sciences and Engineering (BESE) Division

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