During meiosis, cohesins—protein complexes that hold sister chromatids together—are lost from chromosomes in a step-wise manner1. Loss of cohesins from chromosome arms is necessary for homologous chromosomes to segregate during meiosis I. Retention of cohesins around centromeres until meiosis II is required for the accurate segregation of sister chromatids. Here we show that phosphorylation of the cohesin subunit Rec8 contributes to step-wise cohesin removal. Our data further implicate two other key regulators of meiotic chromosome segregation, the cohesin protector Sgo1 and meiotic recombination in bringing about the step-wise loss of cohesins and thus the establishment of the meiotic chromosome segregation pattern. Understanding the interplay between these processes should provide insight into the events underlying meiotic chromosome mis-segregation, the leading cause of miscarriages and mental retardation in humans.
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We thank F. Lewitter for help with the Polo kinase substrate consensus sequence analysis, L.-S. Ee for technical assistance, K. Nasmyth and Y. Watanabe for communication of results before publication and B. Lee, A. Marston and members of the Amon Lab for input and critical reading of the manuscript. A.A. is an Investigator of the Howard Hughes Medical Institute. This research was supported by an NIH grant to A.A. and a NSF pre-doctoral fellowship to G.A.B. Author Contributions G.A.B., B.M.K. and A.A. participated in the design of experiments. G.A.B. and B.M.K. performed all non-MS experiments. Y.Z., J.-E.K. and F.W. designed and performed all MS analysis and analysed MS results.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Example of a MS/MS spectrum. (PDF 29 kb)
Coverage of the Rec8 in the various cell cycle arrest. (PDF 92 kb)
Mutation of the phosphorylation sites in Rec8 to alanine interferes with progression through meiosis I. (PDF 66 kb)
Mutations of phosphorylation or cleavage sites of Rec8 interferes with chromosome segregation. (PDF 38 kb)
Metaphase I cells lacking Pds1 accumulate in rec8-17A mutants. (PDF 128 kb)
Recombination allows Rec8 cleavage in rec8-17A and rec8-29A mutants. (PDF 135 kb)
Rec8-17A cleavage in cells expressing a catalytically dead version of SPO11. (PDF 92 kb)
Deletion of SPO11 abolishes step-wise loss of meiotic cohesion. (PDF 73 kb)
Depletion of Sgo1 in spo11-Y135F, rad50S or dmc1Δ mek1Δ mutants allows proper meiosis II chromosome segregation in Sgo1-depleted cells. (PDF 27 kb)
Depletion of Sgo1 partially alleviates the need for Rec8 phosphorylation and Cdc5 in Rec8 cleavage and anaphase I entry. (PDF 142 kb)
Depletion of Sgo1 allows Rec8 removal from chromosomes in Cdc5-depleted cells. (PDF 832 kb)
Rec8 phosphorylation on S136 and S521 is regulated during meiosis. (PDF 40 kb)
Cdc5 independent phosphorylation sites. (DOC 80 kb)
CDC5-dependent phosphorylation sites (PDF 43 kb)
This file contains the Supplementary Methods, Supplementary Figure Legends, Supplementary Table 3 and additional references. (DOC 152 kb)
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Brar, G., Kiburz, B., Zhang, Y. et al. Rec8 phosphorylation and recombination promote the step-wise loss of cohesins in meiosis. Nature 441, 532–536 (2006). https://doi.org/10.1038/nature04794
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