Sister chromatid cohesion and DNArecombination are at the heart of meiosis, which is a key process for gametogenesis. Maintenance ofgenome integrity during gametogenesis is of utmost medical importance, considering the extraordinarily high incidence of aneuploidies in man. Meiotic chromatin dynamics is specifically distinct from mitotic, and is far from being understood. In this application for renewal, we ask for continuous support of our studies on a meiosis-specific cohesin protein, SMCi[3, that we have isolated and initially characterized during the first grant period. SMClp turned out to be a central element of meiotic chromosome behavior. As we showed, SMCifJ is required for sister chromatid cohesion of meiotic chromosomes, for meiosis-specific telomere movements, and for proper meiotic DNA recombination. Molecular, cellular and organismal studies are now needed to decipher the mechanisms through which SMCip works, to put its function into the larger context of meiotic chromosome structure and behavior, and to further elucidate its biological role. Our central hypothesis suggests that SMCi(3 plays a specific and essential role in determining meiotic chromosome structure and dynamics and thus in avoiding aneuploidies. In particular, we propose that SMClp, within specific complexes, contributes to synaptonemal complex formation and the organization of axis and chromatin loops. We also predict that SMClp plays a direct role in telomere function. We further suggest that turnover of the SMCi(3 cohesin complexis key to maintenance of sister chromatid cohesion during female meiosis, specifically dictyate arrest, and thus important to avoid aneuploidies.
Our aim i s to determine the role of SMClp during dictyate arrest and in the age-related increase in aneuploidies. In addition we propose that SMCi|3 fulfills distinct functions from the ubiquitous SMCicx.
Our aim i s to test these hypotheses. Since the available evidence suggests SMCip to be a key protein in mammalian meiosis, our results will be important not only for a better understanding of mammalianSMC protein biology, but also for understanding of meiosis-specificfeatures of chromosome structure, and thus for human reproductive biology and health with particular significance for prevention of aneuploidy. Proper chromosome structure and segregation are essential for meiosis, i.e.gametogenesis. The identification and characterization of proteins required for these processes, such as cohesins, is of paramount importance not only for basic biology, but even more so for human health, since man suffers from an extraordinarilyhigh rates of chromosomal abnormalities that emerge during gametogenesis and cause, for example, Down syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062517-07
Application #
7336274
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Portnoy, Matthew
Project Start
2001-06-01
Project End
2010-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
7
Fiscal Year
2008
Total Cost
$324,169
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Murdoch, Brenda; Owen, Nichole; Stevense, Michelle et al. (2013) Altered cohesin gene dosage affects Mammalian meiotic chromosome structure and behavior. PLoS Genet 9:e1003241
Revenkova, Ekaterina; Herrmann, Kathleen; Adelfalk, Caroline et al. (2010) Oocyte cohesin expression restricted to predictyate stages provides full fertility and prevents aneuploidy. Curr Biol 20:1529-33
Adelfalk, Caroline; Janschek, Johannes; Revenkova, Ekaterina et al. (2009) Cohesin SMC1beta protects telomeres in meiocytes. J Cell Biol 187:185-99
Revenkova, Ekaterina; Focarelli, Maria Luisa; Susani, Lucia et al. (2009) Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA. Hum Mol Genet 18:418-27
Vasileva, Ana; Tiedau, Daniela; Firooznia, Adriana et al. (2009) Tdrd6 is required for spermiogenesis, chromatoid body architecture, and regulation of miRNA expression. Curr Biol 19:630-9
Novak, Ivana; Wang, Hong; Revenkova, Ekaterina et al. (2008) Cohesin Smc1beta determines meiotic chromatin axis loop organization. J Cell Biol 180:83-90
Jessberger, R (2008) New insights into germ cell tumor formation. Horm Metab Res 40:342-6
Jessberger, Rolf (2005) How to divorce engaged chromosomes? Mol Cell Biol 25:18-22
Firooznia, Adriana; Revenkova, Ekaterina; Jessberger, Rolf (2005) From the XXVII North American Testis Workshop: the function of SMC and other cohesin proteins in meiosis. J Androl 26:1-10
Kouznetsova, Anna; Novak, Ivana; Jessberger, Rolf et al. (2005) SYCP2 and SYCP3 are required for cohesin core integrity at diplotene but not for centromere cohesion at the first meiotic division. J Cell Sci 118:2271-8

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