title: The role of break-induced replication in large-scale expansions of (CAG)n/(CTG)nrepeats.
abstract: Expansions of (CAG)n/(CTG)ntrinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are commonly observed in human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism may lead to a large-scale repeat expansion as a single step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n/(CTG)nrepeats in Saccharomyces cerevisiae. The median size of repeat expansions was ∼60 triplets, although we also observed additions of more than 150 triplets. Genetic analysis revealed that Rad51, Rad52, Mre11, Pol32, Pif1, and Mus81 and/or Yen1 proteins are required for large-scale expansions, whereas proteins previously implicated in small-scale expansions are not involved. From these results, we propose a new model for large-scale expansions, which is based on the recovery of replication forks broken at (CAG)n/(CTG)nrepeats via break-induced replication.
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors.forename: Samantha T
authors.initials: ST
authors.lastname: Harris
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Dinter
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors.forename: Kartik A
authors.initials: KA
authors.lastname: Shah
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Mirkin
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D042622:DNA Repeat Expansion; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*
chemical_list: D004271:DNA, Fungal