Recombination-induced CAG trinucleotide repeat expansions in yeast involve the MRE11–RAD50–XRS2 complex

Abstract

Recombination induced by double‐strand breaks (DSBs) in yeast leads to a higher proportion of expansions to contractions than does replication‐associated tract length changes. Expansions are apparently dependent on the property of the repeat array to form hairpins, since DSB repair of a CAA₈₇ repeat induces only contractions of the repeat sequence. DSB‐repair efficiency is reduced by 40% when DNA synthesis must traverse a CAG₉₈ array, as compared with a CAA₈₇ array. These data indicate that repair‐ associated DNA synthesis is inhibited by secondary structures formed by CAG₉₈ and that these structures promote repeat expansions during DSB repair. Overexpression of Mre11p or Rad50p suppresses the inhibition of DSB repair by CAG₉₈ and significantly increases the average size of expansions found at the recipient locus. Both effects are dependent on the integrity of the Mre11p–Rad50p–Xrs2p complex. The Mre11 complex thus appears to be directly involved in removing CAG or CTG hairpins that arise frequently during DNA synthesis accompanying gene conversion of these trinucleotide repeats.