Abstract
ABSTRACTEukaryotic chromosomes are replicated in interphase and the two newly duplicated sister chromatids are held together by the cohesin complex and several cohesin auxiliary factors. Sister chromatid cohesion is essential for accurate chromosome segregation during mitosis, yet has also been implicated in other processes, including DNA damage repair, transcription and DNA replication. To assess how cohesin and associated factors functionally interconnect and coordinate with other cellular processes, we systematically mapped the genetic interactions of 17 cohesin genes centered on quantitative growth measurements of >52,000 gene pairs in the budding yeast Saccharomyces cerevisiae. Integration of synthetic genetic interactions unveiled a cohesin functional map that constitutes 373 genetic interactions, revealing novel functional connections with post-replication repair, microtubule organization and protein folding. Accordingly, we show that the microtubule-associated protein Irc15 and the prefoldin complex members Gim3, Gim4 and Yke2 are new factors involved in sister chromatid cohesion. Our genetic interaction map thus provides a unique resource for further identification and functional interrogation of cohesin proteins. Since mutations in cohesin proteins have been associated with cohesinopathies and cancer, it may also help in identifying cohesin interactions relevant in disease etiology.
Highlights
Sister chromatid cohesion ensures close proximity of the two sister chromatids from the time of replication until their separation to opposite spindle poles during mitosis
Irc15 promotes the loading of centromeric cohesin The cohesin interaction network may reveal new connections between cohesin genes and distinct biological processes, but may uncover new factors involved in sister chromatid cohesion
The network uncovered novel connections for cohesin genes in various cellular processes. It revealed new factors involved in sister chromatid cohesion, namely the microtubule-associated protein Irc15 and the prefoldin complex members Gim3, Gim4 and Yke2
Summary
Sister chromatid cohesion ensures close proximity of the two sister chromatids from the time of replication until their separation to opposite spindle poles during mitosis. In budding yeast (Saccharomyces cerevisiae), Smc, Smc, Scc and Scc make up the core of the cohesin complex, which is loaded onto chromatin during G1 phase. It forms a ring-like structure that encircles sister chromatids generated during DNA replication in S phase in a manner dependent on Smc acetylation by Eco. Several accessory proteins have been implicated in promoting sister chromatid cohesion, including Elg, Ctf, the alternative replication factor C (RFC) complexes, the replisome component Ctf, the Chl helicase-like protein, the chromatin remodeler Chd and the S phase checkpoint proteins Mrc and Tof (Petronczki et al, 2004; Parnas et al, 2009; Hanna et al, 2001; Skibbens, 2004; Xu et al, 2004; Boginya et al, 2019). Sister chromatid cohesion is dissolved at the metaphase to anaphase transition by proteolytic activity of Esp towards Scc (Uhlmann et al, 1999; Cohen-Fix et al, 1996; Xiong and Gerton, 2010)
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