Abstract
Maintenance and timely termination of cohesion on chromosomes ensures accurate chromosome segregation to guard against aneuploidy in mammalian oocytes and subsequent chromosomally abnormal pregnancies. Sororin, a cohesion stabilizer whose relevance in antagonizing the anti-cohesive property of Wings-apart like protein (Wapl), has been characterized in mitosis; however, the role of Sororin remains unclear during mammalian oocyte meiosis. Here, we show that Sororin is required for DNA damage repair and cohesion maintenance on chromosomes, and consequently, for mouse oocyte meiotic program. Sororin is constantly expressed throughout meiosis and accumulates on chromatins at germinal vesicle (GV) stage/G2 phase. It localizes onto centromeres from germinal vesicle breakdown (GVBD) to metaphase II stage. Inactivation of Sororin compromises the GVBD and first polar body extrusion (PBE). Furthermore, Sororin inactivation induces DNA damage indicated by positive γH2AX foci in GV oocytes and precocious chromatin segregation in MII oocytes. Finally, our data indicate that PlK1 and MPF dissociate Sororin from chromosome arms without affecting its centromeric localization. Our results define Sororin as a determinant during mouse oocyte meiotic maturation by favoring DNA damage repair and chromosome separation, and thereby, maintaining the genome stability and generating haploid gametes.
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Acknowledgments
The present research has received the funding from National Natural Science Foundation of China (Grant No. 31071273 and 31171378) and Fundamental Research Funds for the Central Universities (Program NO. 2014PY045). C.J.H. and Y.F.Y. appreciate the support from State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University.
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C.J.H., Y.F.Y., and L.J. H conceived and designed the experiments; C.J.H. and Y.F.Y. performed experiments; C.J.H., D.W. and F.A.K analyzed the data; D.W., F.A.K., and X.F.J. contributed reagents/materials/analysis tools; C.J.H. and D. W wrote; and C.J.H., F.A.K., and L.J. H revised the paper.
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Editor: Tetsuji Okamoto
Chun-Jie Huang and Yi-Feng Yuan equally contributed to this work.
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Figure S1
Schematic diagram of step-wise loss of cohesion during meiosis in mouse oocytes. Cohesion (orange rings that entrap sister chromatids) in oocytes is established during pre-meiotic S phase of prophase I, which holds homologs together throughout the protracted prophase I arrest at dictyate stage. The “cohesive” cohesion is granted by recruitment of Sororin due to acetylation of Smc3 by Esco1/2 during S phase (the mechanism by which Sororin antagonizes Wapl-dependent anti-cohesive activity is boxed). Cleavage of cohesion on chromosome arms is conferred by mitotic kinases while its centromeric retention on sister chromatids is safeguarded by protein phosphatase 2 A (PP2A)-SGOL1 complex to entitle homologs to segregate as a syncytium during meiosis I. Release of centromeric cohesion on sisters is executed by separase to segregate sister chromatids during meiosis II. Precocious loss of centromeric cohesion during meiosis I and/or meiosis II will contribute to aneploidy in eggs, which leads to infertility, miscarriage, birth defects, and other reproductive/developmental disorders in human. (JPEG 2800 kb)
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Huang, CJ., Yuan, YF., Wu, D. et al. The cohesion stabilizer sororin favors DNA repair and chromosome segregation during mouse oocyte meiosis. In Vitro Cell.Dev.Biol.-Animal 53, 258–264 (2017). https://doi.org/10.1007/s11626-016-0107-0
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DOI: https://doi.org/10.1007/s11626-016-0107-0