BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis

Broering, Tyler J.; Alavattam, Kris G.; Sadreyev, Ruslan I.; Ichijima, Yosuke; Kato, Yasuko; Hasegawa, Kazuteru; Camerini‐Otero, R. Daniel; Lee, Jeannie T.; Andreassen, Paul R.; Namekawa, Satoshi H.

doi:10.1083/jcb.201311050

Cited by 83 publications

(98 citation statements)

References 74 publications

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“…This is a meiotic specific process that uses the DNA damage response to recognize unsynapsed regions and reconfigure their chromatin to a silent epigenetic domain named the sex body. The act of silencing is itself dependent upon phosphorylation of histone H2AX (γ-H2AX) by ATR in a BRCA1-dependent manner45. We performed γ-H2AX labelling of mutant spermatocytes and found moderate staining of the X and Y chromosomes in those cells showing aligned sex chromosomes.…”

Section: Resultsmentioning

confidence: 92%

C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

et al. 2016

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Meiotic recombination generates crossovers between homologous chromosomes that are essential for genome haploidization. The synaptonemal complex is a ‘zipper'-like protein assembly that synapses homologue pairs together and provides the structural framework for processing recombination sites into crossovers. Humans show individual differences in the number of crossovers generated across the genome. Recently, an anonymous gene variant in C14ORF39/SIX6OS1 was identified that influences the recombination rate in humans. Here we show that C14ORF39/SIX6OS1 encodes a component of the central element of the synaptonemal complex. Yeast two-hybrid analysis reveals that SIX6OS1 interacts with the well-established protein synaptonemal complex central element 1 (SYCE1). Mice lacking SIX6OS1 are defective in chromosome synapsis at meiotic prophase I, which provokes an arrest at the pachytene-like stage and results in infertility. In accordance with its role as a modifier of the human recombination rate, SIX6OS1 is essential for the appropriate processing of intermediate recombination nodules before crossover formation.

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Section: Resultsmentioning

confidence: 92%

C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

et al. 2016

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“…Like ATR, the DNA repair protein BRCA1 is an essential component of MSCI/MSUC activation, and one of the earliest cytological markers of asynapsed chromosomes. Although the bestcharacterized role of BRCA1 in somatic DNA damage responses is in promoting the repair of DSBs by homologous recombination, its function during MSCI/MSUC appears distinct from the recognition or repair of SPO11-dependent meiotic DSBs (Mahadevaiah et al, 2008;Broering et al, 2014). Therefore, how BRCA1 participates in the detection of asynapsed chromatin to trigger ATR recruitment remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of exon 11 from the Brca1 gene in the male germline compromises the activation of MSCI: ATR recruitment and H2AFX phosphorylation are reduced, but not entirely ablated, leading to MSCI failure. Despite this requirement, it has been shown that other events in the early stages of MSCI, such as recruitment of the HORMAD proteins, is unaffected by the Brca1 mutation (Broering et al, 2014). Therefore, additional, BRCA1-independent mechanisms are likely to participate in ATR activation during MSCI/MSUC.…”

Section: Introductionmentioning

confidence: 99%

“…Despite its importance, the signal to which ATR is recruited during the early stages of MSCI remains undefined. Experimental evidence has suggested that initiation of MSCI is at least partially dependent on the BRCA1 protein (Turner et al, 2004;Broering et al, 2014). Together with ATR, localization of BRCA1 to asynapsed chromatin is an early event in meiosis.…”

Section: Introductionmentioning

confidence: 99%

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Key mediators of somatic ATR signaling localize to unpaired chromosomes in spermatocytes

et al. 2015

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Meiotic silencing of unpaired chromatin (MSUC) occurs during the first meiotic prophase, as chromosomes that fail to pair are sequestered into a transcriptionally repressive nuclear domain. This phenomenon is exemplified by the heterologous sex chromosomes of male mammals, where the ATR DNA damage response kinase is crucial for this silencing event. However, the mechanisms underlying the initiation of MSUC remain unknown. Here, we show that essential components of ATR signaling in murine somatic cells are spatially confined to unpaired chromosomes in spermatocytes, including the ATR-dependent phosphorylation of the single-stranded DNA (ssDNA)-binding complex replication protein A (RPA) and the checkpoint kinase CHK1. These observations support a model in which ssDNA plays a central role in the recruitment of ATR during MSUC, and provide a link to meiotic progression through activation of CHK1.

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“…Importantly, there is a group of sex-linked genes that escape postmeiotic silencing and become expressed in postmeiotic spermatids (reviewed elsewhere (Sin and Namekawa 2013)). The regulatory mechanisms by which sex-linked genes are inactivated by MSCI and activated to escape postmeiotic silencing were identified as DNA damage response pathways adopted from somatic machinery to recognize damaged DNA (Broering, et al 2014, Ichijima, et al 2011, Sin, et al 2012a, Turner, et al 2004). The genes that escape postmeiotic silencing, termed escape genes, include most of the ampliconic/multi-copy genes, as well as many single-copy genes, on both X and Y chromosomes (Cocquet, et al 2009, Mueller, et al 2008, Sin, et al 2012b, Toure, et al 2004a).…”

Section: Introductionmentioning

confidence: 99%

Functional significance of the sex chromosomes during spermatogenesis

Namekawa

2015

Reproduction

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Mammalian sex chromosomes arose from an ordinary pair of autosomes. Over hundreds of millions of years, they have evolved into highly divergent X and Y chromosomes and have become increasingly specialized for male reproduction. Both sex chromosomes have acquired and amplified testis-specific genes, suggestive of roles in spermatogenesis. To understand how the sex chromosome genes participate in the regulation of spermatogenesis, we review genes, including single-copy, multi-copy, and ampliconic genes, whose spermatogenic functions have been demonstrated in mouse genetic studies. Sex chromosomes are subject to chromosome-wide transcriptional silencing in meiotic and postmeiotic stages of spermatogenesis. We also discuss particular sex-linked genes that escape postmeiotic silencing and their evolutionary implications. The unique gene contents and genomic structures of the sex chromosomes reflect their strategies to express genes at various stages of spermatogenesis and reveal the driving forces that shape their evolution.

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BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis

Abstract: The major role of BRCA1 in meiosis is not in meiotic recombination but instead in promotion of the dramatic chromatin changes required for formation and function of the XY body.

Cited by 83 publications

References 74 publications

C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility

Key mediators of somatic ATR signaling localize to unpaired chromosomes in spermatocytes

Functional significance of the sex chromosomes during spermatogenesis

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