Rai R, Laloraya S

Replication of linear chromosomes is facilitated by firing of multiple replication origins that ensures timely duplication of the entire chromosome. The Smc5/6 complex is thought to play an important role in replication by its involvement in the restart of collapsed replication forks. Here, we present genetic evidence for functional interaction ...

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between replication origin distribution and two subunits of the Smc5/6 complex, Smc6 and Mms21, as well as Top1. An artificial chromosome that has a long arm having low origin density (5ori∆YAC) is relatively unstable compared to the YAC having normal origin distribution in wild-type cells, but is partially stabilized in smc6-56 and top1∆ mutants. While a SUMO-ligase-deficient mutant of Mms21 does not affect stability of the 5ori∆YAC by itself, in combination with top1∆, the 5ori∆YAC is destabilized as evidenced by increased chromosome loss frequency in the mms21∆sl top1∆ double mutant. Likewise, the smc6-56 top1∆ double mutant also exhibits enhanced destabilization of the 5ori∆YAC compared to either single mutant. Such an increase in chromosome loss is not observed for a similar YAC that retains the original replication origins and normal origin distribution on the long arm, in either double mutant having the mms21∆sl or smc6-56 mutations in combination with top1∆. Our findings reveal a requirement for the Smc5/6 complex, including Mms21/Nse2 mediated sumoylation, and topoisomerase-1 (Top1), for maintaining stability of a chromosome having low origin density and suggest a functional cooperation between the Smc5/6 complex and Top1 in maintenance of topologically challenged chromosomes prone to replication fork collapse or accumulation of torsional stress.

Date: Feb. 16, 2017

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