DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line

ElInati, Elias; Russell, H. R.; Ojarikre, Obah A.; Sangrithi, Mahesh N.; Hirota, Takayuki; Rooij, Dirk G. de; McKinnon, Peter J.; Turner, James M. A.

doi:10.1073/pnas.1712530114

Cited by 49 publications

(48 citation statements)

References 76 publications

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“…We complemented our transcriptomic analysis with RNA-FISH for the X gene Scml2 and the Y gene Zfy2 . These genes are silenced at pachynema in control males but not in MSCI mutants ( ElInati et al., 2017 , Royo et al., 2010 , Bhattacharyya et al., 2013 , Royo et al., 2013 ). Following RNA-FISH, early pachytene cells were identified using HORMAD2 immunostaining, as described previously ( Cloutier et al., 2015 , Cloutier et al., 2016 ).…”

Section: Resultsmentioning

confidence: 97%

“…Mechanistically, meiotic silencing initiates from recombinational DNA double-strand breaks (DSBs) that are located within asynapsed chromosome axes ( ElInati et al., 2017 , Carofiglio et al., 2013 , Schoenmakers et al., 2008 ). Supported by SYCP3 and HORMAD1/2, BRCA1-A complex components and ATR localize to these DSBs and thereafter spread along the full length of asynapsed chromosome axes ( Lu et al., 2013 , Royo et al., 2013 , Wojtasz et al., 2012 , Daniel et al., 2011 , Kouznetsova et al., 2009 , Sciurano et al., 2007 , Turner et al., 2004 , Xu et al., 2003 ).…”

Section: Introductionmentioning

confidence: 99%

“…Supported by SYCP3 and HORMAD1/2, BRCA1-A complex components and ATR localize to these DSBs and thereafter spread along the full length of asynapsed chromosome axes (Lu et al., 2013, Royo et al., 2013, Wojtasz et al., 2012, Daniel et al., 2011, Kouznetsova et al., 2009, Sciurano et al., 2007, Turner et al., 2004, Xu et al., 2003). Subsequently, facilitated by MDC1 (Ichijima et al., 2011) and TOPBP1 (ElInati et al., 2017), ATR spreads into chromatin loops, catalyzing serine-139 phosphorylation of histone H2AX (Cloutier et al., 2015, Fernandez-Capetillo et al., 2003) (γH2AX; Figure 1A).

Figure 1DNA Damage Response Factors Direct H3K9me3 Acquisition on the X Chromosome(A) Schematic of the MSCI pathway.(B–F) Early pachytene spermatocytes from control (B, n = 38 cells), Hormad2 KO (C, n = 32 cells), Brca1 Δ11 (D, n = 17 cells), Atr cKO (E, n = 20 cells), and H2afx KO (F, n = 34 cells) immunostained for SYCP3 (green) and H3K9me3 (magenta). Dashed rectangles highlight XY pair, which is magnified in right panels.…”

Section: Introductionmentioning

confidence: 99%

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SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice

et al. 2018

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SummaryMeiotic synapsis and recombination ensure correct homologous segregation and genetic diversity. Asynapsed homologs are transcriptionally inactivated by meiotic silencing, which serves a surveillance function and in males drives meiotic sex chromosome inactivation. Silencing depends on the DNA damage response (DDR) network, but how DDR proteins engage repressive chromatin marks is unknown. We identify the histone H3-lysine-9 methyltransferase SETDB1 as the bridge linking the DDR to silencing in male mice. At the onset of silencing, X chromosome H3K9 trimethylation (H3K9me3) enrichment is downstream of DDR factors. Without Setdb1, the X chromosome accrues DDR proteins but not H3K9me3. Consequently, sex chromosome remodeling and silencing fail, causing germ cell apoptosis. Our data implicate TRIM28 in linking the DDR to SETDB1 and uncover additional factors with putative meiotic XY-silencing functions. Furthermore, we show that SETDB1 imposes timely expression of meiotic and post-meiotic genes. Setdb1 thus unites the DDR network, asynapsis, and meiotic chromosome silencing.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice

et al. 2018

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“…Ensuing heterochromatinization results in exclusion of RNA Pol II. Persistent DSBs within unsynapsed regions, both SPO11dependent and independent, are thought to serve as initiation sites for meiotic silencing (Carofiglio et al 2013;ElInati et al 2017). However, the enrichment of DSB markers observed within silenced regions is also likely to reflect the inhibitory role of HORMADs on DSB repair.…”

Section: Meiotic Silencing Is Mediated By Hormads Andmentioning

confidence: 99%

Oocyte Quality Control: Causes, Mechanisms, and Consequences

Hunter

2017

Cold Spring Harb Symp Quant Biol

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Oocyte quality and number are key determinants of reproductive life span and success. These variables are shaped in part by the elimination of oocytes that experience problems during the early stages of meiosis. Meiotic prophase-I marks an extended period of genome vulnerability in which epigenetic reprogramming unleashes retroelements and hundreds of DNA double-strand breaks (DSBs) are inflicted to initiate the programmed recombination required for accurate chromosome segregation at the first meiotic division. Expression of LINE-1 retroelements perturbs several aspects of meiotic prophase and is associated with oocyte death during the early stages of meiotic prophase I. Defects in chromosome synapsis and recombination also trigger oocyte loss, but typically at a later stage, as cells transition into quiescence and form primordial follicles. Interrelated pathways that signal defects in DSB repair and chromosome synapsis mediate this late oocyte attrition. Here, I review our current understanding of early and late oocyte attrition based on studies in mouse and describe how these processes appear to be both distinct and overlapping and how they help balance the quality and size of oocyte reserves to maximize fecundity.

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“…This wave of H2AX phosphorylation can be observed in Atm- deficient spermatocytes at early-mid zygonema and is lost when Spo11 or Atr is deleted [ 11 – 13 ]. The third wave is also mediated by ATR and marks chromatin associated with unsynapsed axes at the zygotene/pachytene transition [ 14 , 15 ]. Unlike the first two waves of H2AX phosphorylation expansion at leptonema and zygonema, the third wave can be observed in Spo11 -deficient spermatocytes [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

MOF influences meiotic expansion of H2AX phosphorylation and spermatogenesis in mice

et al. 2018

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Three waves of H2AX phosphorylation (γH2AX) have been observed in male meiotic prophase I: the first is ATM-dependent and occurs at leptonema, while the second and third are ATR-dependent, occuring at zygonema and pachynema, respectively. The third wave of H2AX phosphorylation marks and silences unsynapsed chromosomes. Little is known about H2AX phosphorylation expands to chromatin-wide regions in spermatocytes. Here, we report that histone acetyltransferase (HAT) MOF is involved in all three waves of H2AX phosphorylation expansion. Germ cell-specific deletion of Mof in spermatocytes by Stra8-Cre (Mof cKO) caused global loss of H4K16ac. In leptotene and zygotene spermatocytes of cKO mice, the γH2AX signals were observed only along the chromosomal axes, and chromatin-wide H2AX phosphorylation was lost. In almost 40% of early-mid pachytene spermatocytes from Mof cKO mice, γH2AX and MDC1 were detected along the unsynapsed axes of the sex chromosomes, but failed to expand, which consequently caused meiotic sex chromosome inactivation (MSCI) failure. Furthermore, though RAD51 was proficiently recruited to double-strand break (DSB) sites, defects in DSB repair and crossover formation were observed in Mof cKO spermatocytes, indicating that MOF facilitates meiotic DSB repair after RAD51 recruitment. We propose that MOF regulates male meiosis and is involved in the expansion of all three waves of H2AX phosphorylation from the leptotene to pachytene stages, initiated by ATM and ATR, respectively.

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DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line

Cited by 49 publications

References 76 publications

SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice

SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice

Oocyte Quality Control: Causes, Mechanisms, and Consequences

MOF influences meiotic expansion of H2AX phosphorylation and spermatogenesis in mice

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