ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing.
ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing.
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DOI：
10.1101/gad.219477.113
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发表时间：
2013-07-01
影响因子：
10.5
通讯作者：
Turner JM
中科院分区：
文献类型：
--
作者：
Royo H;Prosser H;Ruzankina Y;Mahadevaiah SK;Cloutier JM;Baumann M;Fukuda T;Höög C;Tóth A;de Rooij DG;Bradley A;Brown EJ;Turner JM
Homologs that fail to synapse during mammalian meiosis are transcriptionally inactivated via meiotic silencing, an epigenetic mechanism critical to fertility. Checkpoint protein ATR localizes to unsynapsed chromosomes, but its role in meiotic silencing is poorly defined. Using a strategy to temporarily delete ATR in the germline, Royo et al. show that ATR first regulates unsynapsed chromosome sensing and later transduces signals to the surrounding chromatin. This study reveals multiple roles for ATR in meiotic silencing and presents a novel gene ablation technique. 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.
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影响因子：
16
作者：
Lou, ZK;Minter-Dykhouse, K;Chen, JJ
通讯作者：
Chen, JJ
DOI：
10.1073/pnas.0910267107
发表时间：
2010-02-02
影响因子：
11.1
作者：
An, Jee Young;Kim, Eun-A.;Kwon, Yong Tae
通讯作者：
Kwon, Yong Tae
影响因子：
5.3
作者：
Baarends, WM;Wassenaar, E;Grootegoed, JA
通讯作者：
Grootegoed, JA
影响因子：
4.5
作者：
Fukuda T;Pratto F;Schimenti JC;Turner JM;Camerini-Otero RD;Höög C
通讯作者：
Höög C
影响因子：
2.7
作者：
Baarends, WM;Hoogerbrugge, TW;Grootegoed, JA
通讯作者：
Grootegoed, JA