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Homology recognition and DNA double-strand break repair during meiosis

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Title Homology recognition and DNA double-strand break repair during meiosis
Period 10 / 2009 - unknown
Status Current
Research number OND1337062
Data Supplier NWO

Abstract

Meiosis involves two specialized divisions that generate four haploid gametes from a single diploid cell. In preparation for the first meiotic division, homologous chromosomes need to pair and recombine. Homologous chromosome pairing requires the formation and repair of meiotic DNA double-strand breaks (DSBs). The topoisomerase-like enzyme SPO11 makes the DSBs, and the recombinase RAD51 and its meiosis-specific paralogue DMC1 are involved in homology recognition and strand invasion. Pairing culminates in the formation of the synaptonemal complex (SC) between the homologous chromosomes. This project aims to unravel the nature of the link between homologous chromosome recognition, meiotic DSB repair, and progression of synapsis. We will focus on he role of SPO11 and RAD51 in these interdependent processes. Through the use of high resolution 4Pi microscopy, we wish to determine the relative contribution of SPO11-independent processes to homologous chromosome pairing, in fixed Spo11 mutant cells. Further insight into the dynamics of homologous chromosome pairing will be obtained by confocal laser scanning microscopic analyses of living male and female meiotic prophase cells from transgenic mice that express a fluorescent-tagged component of the SC. The role of RAD51 in meiosis will be analysed via a conditional knockout strategy. Induction of exogenous DSBs will be used to decipher the specialized functions of meiotic DSB repair in pairing. Careful analyses of DNA repair in Spo11 mutant spermatocytes and oocytes will unravel the contribution of (meiotic) DSB repair to the detection of nonhomologous chromatin and associated meiotic silencing of unsynapsed chromatin.

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Project leader Dr.ir. W.M. Baarends

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