Although it was not clear that Mnd1 knockout mice would be substantially different from Hop2 mice it has now become clear that these mice are a treasure trove of genetic information about mammalian meiosis. Unlike the Hop2 mice, the Mnd1 mice have a significant proportion of spermatocyte nuclei that show homologously paired chromosome synapsis,repair all their double-strand breaks progress up to late pachytene but do not show any crossovers. These results strongly suggest that, as has been proposed for budding yeast, there are two main pathways (DSBR, Double-Strand Break Repair and SDSA, Strand Displacement and Strand-Annealing) for the repair of double-strand breaks in mice (DSBR leads to mainly crossovers and SDSA results in non-crossovers exclusively) and that Hop2 can act on both pathways. This mouse might also provide insights into how chromosome interactions are channeled primarily between homologs versus sisters, a fundamental requirement leading to the crossovers that ensure the proper segregation of chromosomes. Recently, we have confirmed that Hop2 is only expressed in those Mnd1 knockout spermatocytes that synapse their chromosomes completely. This finding strongly suggests that Hop2 is responsible for this synapsis and since these spermatocytes that show complete synapsis have proceeded to a stage late in pachytene when crossovers would have normally appeared, this finding also indicates that the repair has occurred via the SDSA. We have also shown that although the involvement of Hop2 in the SDSA pathway has been revealed in the Mnd1 knockout background, Hop2 is most likely involved in this pathway in the wild-type mouse as there is 2 to 3 times as much Hop2 protein as there is Mnd1 protein in wild-type spermatocytes, that is, there is an excess of Hop2 beyond that required to form the Hop2/Mnd1 heterodimer that functions to stimulate the RecA-like recombinases, Rad51 and Dmc1. Recently, we have established that in mice there is DSB-independent pairing of homologous chromosomes that occurs before DSBs are introduced. Interestingly, a function for Spo11, the type II-like topoisomerase that introduces the breaks, which is independent of its DSB activity appears to be important for this early homologous pairing.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2010
Total Cost
$382,519
Indirect Cost
City
State
Country
Zip Code
Dai, Jieqiong; Voloshin, Oleg; Potapova, Svetlana et al. (2017) Meiotic Knockdown and Complementation Reveals Essential Role of RAD51 in Mouse Spermatogenesis. Cell Rep 18:1383-1394
Bugreev, Dmitry V; Huang, Fei; Mazina, Olga M et al. (2014) HOP2-MND1 modulates RAD51 binding to nucleotides and DNA. Nat Commun 5:4198
Pezza, Roberto J; Voloshin, Oleg N; Volodin, Alexander A et al. (2014) The dual role of HOP2 in mammalian meiotic homologous recombination. Nucleic Acids Res 42:2346-57
Broering, Tyler J; Alavattam, Kris G; Sadreyev, Ruslan I et al. (2014) BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis. J Cell Biol 205:663-75
Moktan, Hem; Guiraldelli, Michel F; Eyster, Craig A et al. (2014) Solution structure and DNA-binding properties of the winged helix domain of the meiotic recombination HOP2 protein. J Biol Chem 289:14682-91
Margolin, Gennady; Khil, Pavel P; Kim, Joongbaek et al. (2014) Integrated transcriptome analysis of mouse spermatogenesis. BMC Genomics 15:39
Zhao, Weixing; Saro, Dorina; Hammel, Michal et al. (2014) Mechanistic insights into the role of Hop2-Mnd1 in meiotic homologous DNA pairing. Nucleic Acids Res 42:906-17
Naumova, Anna K; Fayer, Shawn; Leung, Jacky et al. (2013) Dynamics of response to asynapsis and meiotic silencing in spermatocytes from Robertsonian translocation carriers. PLoS One 8:e75970
Boateng, Kingsley A; Bellani, Marina A; Gregoretti, Ivan V et al. (2013) Homologous pairing preceding SPO11-mediated double-strand breaks in mice. Dev Cell 24:196-205
Fukuda, Tomoyuki; Pratto, Florencia; Schimenti, John C et al. (2012) Phosphorylation of chromosome core components may serve as axis marks for the status of chromosomal events during mammalian meiosis. PLoS Genet 8:e1002485

Showing the most recent 10 out of 16 publications