SUMO-mediated recruitment allows timely function of the Yen1 nuclease in mitotic cells

Author summaryThe modification of proteins with the small SUMO peptide enables the appropriate localization and correct organization of multiple factors during the repair of DNA damages, including double-strand breaks that could sever the DNA molecule that contains the genetic information of cells. In this work, we describe how the Yen1 protein, a DNA repair factor involved in the last steps of the key DNA repair mechanism called homologous recombination, is controlled by SUMO modification and by its ability to contact other SUMO-modified proteins through specific SUMO interaction motifs (SIMs) in its C-terminal domain. Impairing the SUMO interactions mediated by Yen1's SIMs results in a deficient function of this factor during the resolution of joint DNA molecules that would otherwise prevent the chromosomes to fully separate and segregate to the two daughter cells during each cell division. In living cells, this defect in Yen1 functions related to the absence of interaction with SUMO results in defective protein localization, increased sensitivity to DNA damaging agents, and increased chromosome segregation problems. This SUMO-mediated control mechanism of the Yen1 nuclease is thus important to preserve genome integrity. The post-translational modification of DNA damage response proteins with SUMO is an important mechanism to orchestrate a timely and orderly recruitment of repair factors to damage sites. After DNA replication stress and double-strand break formation, a number of repair factors are SUMOylated and interact with other SUMOylated factors, including the Yen1 nuclease. Yen1 plays a critical role in ensuring genome stability and unperturbed chromosome segregation by removing covalently linked DNA intermediates between sister chromatids that are formed by homologous recombination. Here we show how this important role of Yen1 depends on interactions mediated by non-covalent binding to SUMOylated partners. Mutations in the motifs that allow SUMO-mediated recruitment of Yen1 impair its ability to resolve DNA intermediates and result in chromosome mis-segregation and increased genome instability.