Abstract
Evidence from lower eukaryotes suggests that the chromosomal associations of all the structural maintenance of chromosome (SMC) complexes, cohesin, condensin and Smc5/6, are influenced by the Nipbl/Mau2 heterodimer. Whether this function is conserved in mammals is currently not known. During mammalian meiosis, very different localisation patterns have been reported for the SMC complexes, and the localisation of Nipbl/Mau2 has just recently started to be investigated. Here, we show that Nipbl/Mau2 binds on chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes. In spermatocytes, Nipbl/Mau2 then relocalises to chromocenters, whereas in oocytes it remains bound to chromosomal axes throughout prophase to dictyate arrest. The localisation pattern of Nipbl/Mau2, together with those seen for cohesin, condensin and Smc5/6 subunits, is consistent with a role as a loading factor for cohesin and condensin I, but not for Smc5/6. We also demonstrate that Nipbl/Mau2 localises next to Rad51 and γH2AX foci. NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I. However, this is insufficient to result in major meiotic malfunctions, and the chromosomal associations of the synaptonemal complex proteins and the three SMC complexes appear cytologically indistinguishable in wild-type and Nipbl +/− spermatocytes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00412-013-0444-7) contains supplementary material, which is available to authorized users.
Highlights
The structural maintenance of chromosome (SMC) complexes regulate several aspects of chromosome dynamics during the eukaryotic cell cycle
NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I
The chromosomal association of cohesin is governed by the evolutionary conserved loading complex, which consists of a heterodimer between the Nipbl and Mau2 proteins (Michaelis et al 1997; Ciosk et al 2000)
Summary
The structural maintenance of chromosome (SMC) complexes regulate several aspects of chromosome dynamics during the eukaryotic cell cycle. Nipbl and Mau interact with each other through their conserved N-terminal domains (Bermudez et al 2012; Seitan et al 2006) and associate with mitotic chromosomes from telophase until prophase, when the complex is excluded from chromatin (Watrin et al 2006) Both Nipbl and Mau are essential due to their role in sister chromatid cohesion and segregation. In C. elegans, a mutation in Scc abolishes loading of cohesin, but not the other SMC complexes to chromosome axes, leading to multiple cytological defects and a failure to repair SPO11-induced breaks (Lightfoot et al 2011). We have determined the meiotic localisation of Nipbl and Mau in wild-type and Nipbl+/− mouse germ cells and their associations with the SC, cohesin, condensin and the Smc5/6 complex, as well as markers of DNA damage and repair
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