BRCA1-mediated chromatin silencing is limited to oocytes with a small number of asynapsed chromosomes

Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, S-171 77, Sweden.
Journal of Cell Science (Impact Factor: 5.43). 07/2009; 122(Pt 14):2446-52. DOI: 10.1242/jcs.049353
Source: PubMed


Transcriptional silencing of the sex chromosomes during male meiosis is regarded as a manifestation of a general mechanism active in both male and female germ cells, called meiotic silencing of unsynapsed chromatin (MSUC). MSUC is initiated by the recruitment of the tumor suppressor protein BRCA1 to the axes of unsynapsed chromosomes. We now show that Sycp3, a structural component of the chromosome axis, is required for localization of BRCA1 to unsynapsed pachytene chromosomes. Importantly, we find that oocytes carrying an excess of two to three pairs of asynapsed homologous chromosomes fail to recruit enough BRCA1 to the asynapsed axes to activate MSUC. Furthermore, loss of MSUC function only transiently rescues oocytes from elimination during early postnatal development. The fact that the BRCA1-dependent synapsis surveillance system cannot respond to higher degrees of asynapsis and is dispensable for removal of aberrant oocytes argues that MSUC has a limited input as a quality control mechanism in female germ cells.

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    • "On one hand, the presence of important genes in those regions subjected to inactivation may result in cellular dysfunction (Turner et al. 2004, 2006). On the other hand, the diversion of inactivation factors to unsynapsed autosomes may result in a failure to properly inactivate the sex chromosomes (Kouznetsova et al. 2009; Mahadevaiah et al. 2008). Also, the ectopic association of unsynapsed autosomes with the sex chromosomes may result in a deregulation of MSCI (Homolka et al. 2007). "
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    • "We also labeled fetal oocytes for BRCA1, a component of the synapsis quality control mechanism known as meiotic silencing of unpaired chromatin (MSUC; Ichijima et al., 2011; Mahadevaiah et al., 2008; Schimenti, 2005; Turner, 2007; Turner et al., 2004, 2005). This analysis allows positive identification of even small areas of chromosome asynapsis but is limited to oocytes with asynapsis of fewer than two or three homologous chromosomes (Kouznetsova et al., 2009). This analysis revealed MSUC in 18.2% of WT E18.5 oocytes, suggesting the presence of small areas of asynapsis that could not be reliably identified with SYCP1/SYCP2 costaining (Figures 4C and S3C–S3F; Table S4A). "
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    • "Meiotic silencing involves two sets of proteins: ''sensors,'' which localize to axial elements (AEs) and sense asynapsis, and ''effectors,'' which localize to the chromatin loops associated with unsynapsed AEs, causing gene silencing over a considerable distance. The AE component synaptonemal complex protein 3 (SYCP3) (Kouznetsova et al. 2009), HORMA (Hop1, Rev7, and Mad2) domain proteins HORMAD1 (Daniel et al. 2011) and HORMAD2 (Wojtasz et al. 2012), and breast cancer I gene BRCA1 (Turner et al. 2004) have been identified as sensors: BRCA1 accumulates along unsynapsed AEs in an SYCP3-, HORMAD1-, and HORMAD2-dependent manner, and mice deficient in any of these four proteins exhibit MSCI defects. In contrast, the mediator of DNA damage checkpoint 1 (MDC1) (Ichijima et al. 2011) and histone variant H2AFX (Fernandez-Capetillo et al. 2003) are silencing effectors: In MDC1-and H2AFX-nulls, gene silencing within the chromosome loops does not occur. "
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