Mps2/Kash5 connects the LINC complex to molecular motors on the cytoskeleton to mediate chromosome movements in budding yeast and mouse meiosis

LEE, E;; BISIG, CG,; DITAMO,Y; PEZZA, RJ

Conferencia; 14th Meiosis Gordon Research Conference Molecular Mechanisms and Regulation of Meiosis Across Species; 2018

During the first meiotic prophase chromosomes associate in pairs and recombine, which prepare them for their proper segregation. Concomitantly with these prominent chromosome changes, chromosomes undergo telomere-led rapid chromosome movements (RPMs). RPMs have been seen in all species analyzed so far, and have been proposed to facilitate chromosome interactions and normal levels of recombination. The significance of RPMs is evident as in both yeast and mouse mutation in genes specifically acting in RPMs mechanisms result in meioticfailure. In most organisms RPMs are generated by the cytoskeleton through the nuclear envelope LINC (linker of nucleoskeleton and cytoskeleton) complex. The LINC is formed by the inner nuclear SUN (Sad1-UNC84) domain proteins and outer nuclear membrane KASH (Klarsicht, Anc-1, Syne homology) domain proteins. The SUN proteins are associated with the telomeres while the KASH proteins are connected with cytoskeleton structures. Although of critical importance in maintaining germ cell health, the mechanisms and regulation of RPMs Are still poorly understood. In this work we focused in addressing these important gaps in knowledge. Specifically, to date a Kash5-like protein in S. cerevisiae is missing, and how the yeast LINC complex connect with the relevant cytoskeleton component is not known. Our work identified the yeast Mps2 protein as a Kash5-like protein and reveal Mps2 mechanism of action. We have also identified Myo2, a type V myosin, as an important motor that interacts with Mps2 and direct RPMs in yeast. We propose a model in which that Mps2 and Myo2 cooperate to couple the telomeres to the actin cytoskeleton via LINC complex and promote the chromosome movements in meiotic prophase. We extended our work to mammals. We and others have shown that mouse KASH5, possibly Dynein, and microtubules participate in RPMs. Here, we used a combination of proteomics, biochemical, genetic, and cellular approaches to identify and characterize the function of proteins that link KASH5 to microtubules. Our results identify kinesins (i.e. Kif5b) as novel players that may play a fundamental role in regulating RPMs in mammals. In sum, we have identified critical missing components of the mechanism mediating RPMs in both yeast and mice. We also obtained evidence of their regulatory role on RPMs.