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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1
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Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1

机译:DNA损伤反应蛋白MCPH1对组蛋白变体H2A.X中磷酸丝氨酸和磷酸酪氨酸的双重识别

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摘要

Tyr142, the C-terminal amino acid of histone variant H2A.X is phos-phorylated by WSTF (Williams-Beuren syndrome transcription factor), a component of the WICH complex (WSTF-ISWI chroma-tin-remodeling complex), under basal conditions in the cell. In response to ONA double-strand breaks (DSBs), H2A.X is instantaneously phosphorylated at Ser139 by the kinases ATM and ATR and is progressively dephosphorylated at Tyr142 by the Eya1 and Eya3 tyrosine phosphatases, resulting in a temporal switch from a postulated diphosphorylated (pSer139, pTyr142) to monophos-phorylated (pSer139) H2A.X state. How mediator proteins interpret these two signals remains a question of fundamental interest. We provide structural, biochemical, and cellular evidence that Microcephalin (MCPH1), an early DNA damage response protein, can read both modifications via its tandem BRCA1 C-terminal (BRCT) domains, thereby emerging as a versatile sensor of H2A.X phosphorylation marks. We show that MCPH1 recruitment to sites of DNA damage is linked to both states of H2A.X.
机译:Tyr142是组蛋白变体H2A.X的C末端氨基酸,在基本条件下被WSTF(Williams-Beuren综合征转录因子)(WICH复合物(WSTF-ISWI色度-锡重塑复合物)的组成部分)磷酸化。在牢房里响应ONA双链断裂(DSB),H2A.X在Aer139和ATR激酶处在Ser139处立即磷酸化,并在Eyr1和Eya3酪氨酸磷酸酶处在Tyr142处进行磷酸化处理,从而导致从假定的二磷酸化( pSer139,pTyr142)变为单磷酸化(pSer139)H2A.X状态。介体蛋白如何解释这两个信号仍然是一个基本关注的问题。我们提供的结构,生化和细胞证据表明,Microcephalin(MCPH1)是一种早期的DNA损伤反应蛋白,可以通过其串联的BRCA1 C端(BRCT)域读取两个修饰,从而成为H2A.X磷酸化标记的多功能传感器。我们显示,MCPH1募集到DNA损伤的位点与H2A.X的两个状态都有联系。

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    Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905;

    Howard Hughes Medical Institute and Graduate Program in Biomedical Sciences, University of California at San Diego, School of Medicine, La Jolla, CA 92093;

    Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;

    Departments of Biology and Massachusetts Institute for Technology, Cambridge, MA 02139,Departments of Biological Engineering, Massachusetts Institute for Technology, Cambridge, MA 02139;

    Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;

    Departments of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905;

    Departments of Biology Department, Brookhaven National Laboratory, Upton, NY 11973;

    Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905;

    Departments of Biology and Massachusetts Institute for Technology, Cambridge, MA 02139,Departments of Biological Engineering, Massachusetts Institute for Technology, Cambridge, MA 02139;

    Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;

    Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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