Recombination-induced CAG trinucleotide repeat expansions in yeast involvethe MRE11-RAD50-XRS2 complex

Recombination induced by double-strand breaks (DSBs) in yeast leads to a hi gher proportion of expansions to contractions than does replication-associa ted tract length changes. Expansions are apparently dependent on the proper ty of the repeat array to form hairpins, since DSB repair of a CAA(87) repe at induces only contractions of the repeat sequence. DSB-repair efficiency is reduced by 40% when DNA synthesis must traverse a CAG(98) array, as comp ared with a CAA(87) array. These data indicate that repair-associated DNA s ynthesis is inhibited by secondary structures formed by CAG98 and that thes e structures promote repeat expansions during DSB repair. Overexpression of Mre11p or Rad50p suppresses the inhibition of DSB repair by CAG98 and sign ificantly increases the average size of expansions found at the recipient l ocus. Both effects are dependent on the integrity of the Mre11p-Rad50p-Xrs2 p complex. The Mre11 complex thus appears to be directly involved in removi ng CAG or CTG hairpins that arise frequently during DNA synthesis accompany ing gene conversion of these trinucleotide repeats.