Structural insights into the bypass of the major deaminated purines by translesion synthesis DNA polymerase.
Structural insights into the bypass of the major deaminated purines by translesion synthesis DNA polymerase.
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DOI：
10.1042/bcj20200800
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Jung H;Hawkins M;Lee S
核碱基的环外胺可以通过各种DNA损伤剂如活性氧、一氧化氮和水进行脱氨基作用。鸟嘌呤和腺嘌呤的脱氨基作用分别产生前致突变的黄嘌呤和次黄嘌呤。DNA中碱基的环外胺是氢键的供体，而碱基脱氨产生的羰基部分则是氢键的受体，可以改变嘌呤碱基的配对性质。已知黄嘌呤与胞嘧啶和胸腺嘧啶碱基配对，而次黄嘌呤主要与胞嘧啶配对以促进A至G突变。尽管已知的主要脱氨基嘌呤的promutagenicity，绕过这些病变的DNA聚合酶的结构还没有报道。为了深入了解脱氨基诱导的突变，我们解析了催化黄嘌呤和次黄嘌呤的人DNA聚合酶η（polη）的晶体结构。在polη的催化位点，脱氨基鸟嘌呤（即，黄嘌呤）与引入的dCTP形成三个Watson-Crick样氢键，表明黄嘌呤的O2-烯醇互变异构体参与碱基配对。烯醇互变异构体的形成似乎是由聚合物η的Gln 38的小沟接触促进的。当次黄嘌呤处于模板位置时，脱氨基腺嘌呤利用其O 6-酮互变异构体与引入的dCTP形成两个Watson-Crick氢键，为次黄嘌呤的高前致突变性提供了结构基础。
The exocyclic amines of nucleobases can undergo deamination by various DNA damaging agents such as reactive oxygen species, nitric oxide, and water. The deamination of guanine and adenine generates the promutagenic xanthine and hypoxanthine, respectively. The exocyclic amines of bases in DNA are hydrogen bond donors, while the carbonyl moiety generated by the base deamination acts as hydrogen bond acceptors, which can alter base pairing properties of the purines. Xanthine is known to base pair with both cytosine and thymine, while hypoxanthine predominantly pairs with cytosine to promote A to G mutations. Despite the known promutagenicity of the major deaminated purines, structures of DNA polymerase bypassing these lesions have not been reported. To gain insights into the deaminated-induced mutagenesis, we solved crystal structures of human DNA polymerase η (polη) catalyzing across xanthine and hypoxanthine. In the catalytic site of polη, the deaminated guanine (i.e., xanthine) forms three Watson-Crick-like hydrogen bonds with an incoming dCTP, indicating the O2-enol tautomer of xanthine involves in the base pairing. The formation of the enol tautomer appears to be promoted by the minor groove contact by Gln38 of polη. When hypoxanthine is at the templating position, the deaminated adenine uses its O6-keto tautomer to form two Watson-Crick hydrogen bonds with an incoming dCTP, providing the structural basis for the high promutagenicity of hypoxanthine.