Role of cleavage by separase of the Rec8 kleisin subunit of cohesin during mammalian meiosis I

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Kudo, Nobuaki R. ; Anger, Martin ; Peters, Antoine H. ; Stemmann, Olaf ; Theussl, Hans-Christian ; Helmhart, Wolfgang ; Kudo, Hiromi ; Heyting, Christa ; Nasmyth, Kim:
Role of cleavage by separase of the Rec8 kleisin subunit of cohesin during mammalian meiosis I.
In: Journal of Cell Science. Bd. 122 (2009) Heft 15 . - S. 2686-2698.
ISSN 1477-9137
DOI: https://doi.org/10.1242/jcs.035287

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Abstract

Proteolytic activity of separase is required for chiasma resolution during meiosis I in mouse oocytes. Rec8, the meiosis-specific alpha-kleisin subunit of cohesin, is a key target of separase in yeast. Is the equivalent protein also a target in mammals? We show here that separase cleaves mouse Rec8 at three positions in vitro but only when the latter is hyper-phosphorylated. Expression of a Rec8 variant (Rec8-N) that cannot be cleaved in vitro at these sites causes sterility in male mice. Their seminiferous tubules lack a normal complement of 2 C secondary spermatocytes and 1 C spermatids and contain instead a high proportion of cells with enlarged nuclei. Chromosome spreads reveal that Rec8-N expression has no effect in primary spermatocytes but produces secondary spermatocytes and spermatids with a 4 C DNA content, suggesting that the first and possibly also the second meiotic division is abolished. Expression of Rec8-N in oocytes causes chromosome segregation to be asynchronous and delays its completion by 2-3 hours during anaphase I, probably due to inefficient proteolysis of Rec8-N by separase. Despite this effect, chromosome segregation must be quite accurate as Rec8-N does not greatly reduce female fertility. Our data is consistent with the notion that Rec8 cleavage is important and probably crucial for the resolution of chiasmata in males and females.