BRCA1-mediated chromatin silencing is limited to oocytes with a small number of asynapsed chromosomes
ABSTRACT 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.
- SourceAvailable from: Silvia Garagna
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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). "
ABSTRACT: Many different chromosomal races with reduced chromosome number due to the presence of Robertsonian fusion metacentrics have been described in western Europe and northern Africa, within the distribution area of the western house mouse Mus musculus domesticus. This subspecies of house mouse has become the ideal model for studies to elucidate the processes of chromosome mutation and fixation that lead to the formation of chromosomal races and for studies on the impact of chromosome heterozygosities on reproductive isolation and speciation. In this review, we briefly describe the history of the discovery of the first and subsequent metacentric races in house mice; then, we focus on the molecular composition of the centromeric regions involved in chromosome fusion to examine the molecular characteristics that may explain the great variability of the karyotype that house mice show. The influence that metacentrics exert on the nuclear architecture of the male meiocytes and the consequences on meiotic progression are described to illustrate the impact that chromosomal heterozygosities exert on fertility of house mice-of relevance to reproductive isolation and speciation. The evolutionary significance of the Robertsonian phenomenon in the house mouse is discussed in the final section of this review.Chromosoma 07/2014; 123(6). DOI:10.1007/s00412-014-0477-6 · 3.26 Impact Factor
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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). "
ABSTRACT: Fetal oocyte attrition (FOA) is a conserved but poorly understood process of elimination of more than two-thirds of meiotic prophase I (MPI) oocytes before birth. We now implicate retrotransposons LINE-1 (L1), activated during epigenetic reprogramming of the embryonic germline, in FOA in mice. We show that wild-type fetal oocytes possess differential nuclear levels of L1ORF1p, an L1-encoded protein essential for L1 ribonucleoprotein particle (L1RNP) formation and L1 retrotransposition. We demonstrate that experimental elevation of L1 expression correlates with increased MPI defects, FOA, oocyte aneuploidy, and embryonic lethality. Conversely, reverse transcriptase (RT) inhibitor AZT has a profound effect on the FOA dynamics and meiotic recombination, and it implicates an RT-dependent trigger in oocyte elimination in early MPI. We propose that FOA serves to select oocytes with limited L1 activity that are therefore best suited for the next generation.Developmental Cell 05/2014; 29(5). DOI:10.1016/j.devcel.2014.04.027 · 10.37 Impact Factor
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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. "
ABSTRACT: In mammals, homologs that fail to synapse during meiosis are transcriptionally inactivated. This process, meiotic silencing, drives inactivation of the heterologous XY bivalent in male germ cells (meiotic sex chromosome inactivation [MSCI]) and is thought to act as a meiotic surveillance mechanism. The checkpoint protein ATM and Rad3-related (ATR) localizes to unsynapsed chromosomes, but its role in the initiation and maintenance of meiotic silencing is unknown. Here we show that ATR has multiple roles in silencing. ATR first regulates HORMA (Hop1, Rev7, and Mad2) domain protein HORMAD1/2 phosphorylation and localization of breast cancer I (BRCA1) and ATR cofactors ATR-interacting peptide (ATRIP)/topoisomerase 2-binding protein 1 (TOPBP1) at unsynapsed axes. Later, it acts as an adaptor, transducing signaling at unsynapsed axes into surrounding chromatin in a manner that requires interdependence with mediator of DNA damage checkpoint 1 (MDC1) and H2AFX. Finally, ATR catalyzes histone H2AFX phosphorylation, the epigenetic event leading to gene inactivation. Using a novel genetic strategy in which MSCI is used to silence a chosen gene in pachytene, we show that ATR depletion does not disrupt the maintenance of silencing and that silencing comprises two phases: The first is dynamic and reversible, and the second is stable and irreversible. Our work identifies a role for ATR in the epigenetic regulation of gene expression and presents a new technique for ablating gene function in the germline.Genes & development 07/2013; 27(13):1484-94. DOI:10.1101/gad.219477.113 · 12.64 Impact Factor