Abstract
The repair of double-stranded DNA breaks (DSBs) by homologous recombination involves the formation of branched intermediates that can lead to crossovers following nucleolytic resolution. The nucleases Mus81-Mms4 and Yen1 are tightly controlled during the cell cycle to limit the extent of crossover formation and preserve genome integrity. Here we show that Yen1 is further regulated by sumoylation and ubiquitination. In vivo, Yen1 becomes sumoylated under conditions of DNA damage by the redundant activities of Siz1 and Siz2 SUMO ligases. Yen1 is also a substrate of the Slx5-Slx8 ubiquitin ligase. Loss of Slx5-Slx8 stabilizes the sumoylated fraction, attenuates Yen1 degradation at the G1/S transition, and results in persistent localization of Yen1 in nuclear foci. Slx5-Slx8-dependent ubiquitination of Yen1 occurs mainly at K714 and mutation of this lysine increases crossover formation during DSB repair and suppresses chromosome segregation defects in a mus81∆ background.
Highlights
The repair of double-stranded DNA breaks (DSBs) by homologous recombination involves the formation of branched intermediates that can lead to crossovers following nucleolytic resolution
Homologous recombination (HR) is involved in the repair of double-strand breaks (DSB) generated by endogenous or exogenous sources of DNA damage and it plays an important role in the repair of damage associated with DNA replication[1]
We demonstrate that Yen[1] is a sumoylation target and that Slx5–Slx[8] participates in its regulation by ubiquitination of its lysine 714
Summary
The repair of double-stranded DNA breaks (DSBs) by homologous recombination involves the formation of branched intermediates that can lead to crossovers following nucleolytic resolution. Slx5-Slx8-dependent ubiquitination of Yen[1] occurs mainly at K714 and mutation of this lysine increases crossover formation during DSB repair and suppresses chromosome segregation defects in a mus81Δ background. Some lines of evidence link sumoylation to specific pathways that locally target repair factors to degradation by the action of SUMO-targeted ubiquitin ligases (STUbLs)[27,28] to prevent the toxic effects of their persistent activation. Slx5–Slx[8] prevents persistent accumulation of a fraction of Yen[1] associated with sites of activity in late G2/M and helps maintain the balance between pro- and anti-crossover pathways during HR
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