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Uncovering the polymerase - induced cytotoxicity of an oxidized nucleotide

机译：揭示聚合酶诱导的氧化核苷酸的细胞毒性

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摘要

细胞压力会导致活性氧簇、DNA损伤和基因组不稳定性的积累。一个氧化产物，即8-氧鸟嘌吟(8-oxo-G)，会与腺嘌吟不适当地形成碱基对。因此，了解DNA聚合酶在DNA合成中会怎样利用细胞毒性8-oxo-dGTP核甘酸很重要。现在，Samuel Wilson及同事对结合到基质DNA上的"DNA聚合酶β"在胞嘧啶或腺嘌呤对面插入8-oxo-dGTP的过程做了延时晶体学研究。他们发现，通过吸引另一个二价金属离子，8-oxo-dGTP会促使活性点发生变化，从而避免被作为损伤识别出来。%Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2'-deoxyguanosine, which is found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate Escherichia coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerases discriminate between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine and 8-oxo-dGTP(syn) uses its Hoogsteen edge to base pair with adenine. Here we use time-lapse crystallography to follow 8-oxo-dGTP insertion opposite adenine or cytosine with human pol β,to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen-bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxo-dGTP uses charge modulation during insertion that can lead to a blocked DNA repair intermediate.
机译：细胞压力会导致活性氧簇、DNA损伤和基因组不稳定性的积累。一个氧化产物，即8-氧鸟嘌吟(8-oxo-G)，会与腺嘌吟不适当地形成碱基对。因此，了解DNA聚合酶在DNA合成中会怎样利用细胞毒性8-oxo-dGTP核甘酸很重要。现在，Samuel Wilson及同事对结合到基质DNA上的"DNA聚合酶β"在胞嘧啶或腺嘌呤对面插入8-oxo-dGTP的过程做了延时晶体学研究。他们发现，通过吸引另一个二价金属离子，8-oxo-dGTP会促使活性点发生变化，从而避免被作为损伤识别出来。%Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2'-deoxyguanosine, which is found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate Escherichia coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerases discriminate between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine and 8-oxo-dGTP(syn) uses its Hoogsteen edge to base pair with adenine. Here we use time-lapse crystallography to follow 8-oxo-dGTP insertion opposite adenine or cytosine with human pol β,to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen-bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxo-dGTP uses charge modulation during insertion that can lead to a blocked DNA repair intermediate.

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  • 来源
    《Nature》 |2015年第7536期|635-639a3|共6页
  • 作者

    Bret D. Freudenthal; William A. Beard; Lalith Perera; David D. Shock; Taejin Kim; Tamar Schlick; Samuel H. Wilson;

  • 作者单位

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, North Carolina 27709-2233, USA;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, North Carolina 27709-2233, USA;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, North Carolina 27709-2233, USA;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, North Carolina 27709-2233, USA;

    Department of Chemistry, New York University, and NYU-ECNU Center for Computational Chemistry at NYU Shanghai, 10th Floor Silver Center, 100 Washington Square East, New York, New York 10003, USA,Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, New York 10012, USA;

    Department of Chemistry, New York University, and NYU-ECNU Center for Computational Chemistry at NYU Shanghai, 10th Floor Silver Center, 100 Washington Square East, New York, New York 10003, USA,Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, New York 10012, USA;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, North Carolina 27709-2233, 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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