SUMO E3 ligase Mms21 prevents spontaneous DNA damage induced genome rearrangements

Mms21, a subunit of the Smc5/6 complex, possesses an E3 ligase activity for the Small Ubiquitin-like MOdifier (SUMO), which has a major, but poorly understood role in genome maintenance. Here we show mutations that inactivate the E3 ligase activity of Mms21 cause Rad52- and Pol32-dependent break-induced replication (BIR), which specifically requires the Rrm3 DNA helicase. Interestingly, mutations affecting both Mms21 and the Sgs1 helicase, but not sumoylation of Sgs1, cause further accumulation of genome rearrangements, indicating the distinct roles of Mms21 and Sgs1 in suppressing genome rearrangements. Whole genome sequencing further revealed that the Mre11 endonuclease prevents microhomology-mediated translocations and hairpin-mediated inverted duplications in the mms21 mutant. Consistent with the accumulation of endogenous DNA lesions, mms21 cells accumulate spontaneous Ddc2 foci and display a hyper-activated DNA damage checkpoint. Together, these findings support a new paradigm that Mms21 prevents the accumulation of spontaneous DNA lesions that cause diverse genome rearrangements.