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Structural basis for the suppression of skin cancers by DNA polymerase η

机译：DNA聚合酶η抑制皮肤癌的结构基础

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摘要

DNA polymerase η (Polη) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Polη (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Polη (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Polη to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Polη's action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.
机译：DNA聚合酶η（Polη）在真核聚合酶中是独特的，它具有通过紫外线诱导的环丁烷嘧啶二聚体进行无错复制的熟练能力，并且人类中Polη（又称为POLH）的失活会导致变色干性色素（XPV） 。我们提出与顺式-胸腺嘧啶-胸腺嘧啶（T-T）二聚体和未损坏的DNA的三元复合物中的酿酒酵母Polη（也称为RAD30）的晶体结构。这些结构表明，Polη通过紫外线诱发的病变有效复制的能力源于简单而优雅的机制，其中TT二聚体的两个Ts容纳在比其他聚合酶开放得多的活性位点裂缝中。我们还通过结构，生化和遗传分析表明，通过与Gln 55，Arg 73和Met 74的相互作用，两个Ts在活性位点保持稳定的构型。这些特征共同为Polη对紫外线造成的作用奠定了基础。对抑制日晒的诱变和致癌作用至关重要，从而减少人类皮肤癌的发病率的DNA。

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  • 来源
    《Nature》 |2010年第7301期|P.1039-1043|共5页
  • 作者

    Timothy D. Silverstein; Robert E. Johnson; Rinku Jain; Louise Prakash; Satya Prakash; Aneel K. Aggarwal;

  • 作者单位

    Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677,1425 Madison Avenue, New York, New York 10029, USA;

    Department of Biochemistry and Molecular Biology, 301 University Boulevard, University of Texas Medical Branch, Galveston, Texas 77755-1061, USA;

    Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677,1425 Madison Avenue, New York, New York 10029, USA;

    Department of Biochemistry and Molecular Biology, 301 University Boulevard, University of Texas Medical Branch, Galveston, Texas 77755-1061, USA;

    Department of Biochemistry and Molecular Biology, 301 University Boulevard, University of Texas Medical Branch, Galveston, Texas 77755-1061, USA;

    Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677,1425 Madison Avenue, New York, New York 10029, USA;

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