Structural basis for the suppression of skin cancers by DNA polymerase eta.
Structural basis for the suppression of skin cancers by DNA polymerase eta.
复制标题
作者：
DNA聚合酶η (Polη)在真核生物聚合酶中是独一无二的，它具有通过紫外线诱导的环丁烷嘧啶二聚体进行无错误复制的能力，而Polη在人体内的失活会导致色素干皮病（XPV）的变异形式。本文研究了酵母Polη与顺式胸腺嘧啶-胸腺嘧啶（T-T）二聚体和未损伤DNA的三元配合物的晶体结构。这些结构揭示了Polη在紫外线诱导的损伤中有效复制的能力源于一个简单而优雅的机制，其中T-T二聚体的两个t被容纳在一个比其他聚合酶更开放的活性位点间隙中。我们还通过结构、生化和遗传分析表明，两个t通过与Gln55、Arg73和Met74的相互作用在活性位点保持稳定的构型。总之，这些特征定义了Polη对紫外线损伤DNA的作用的基础，这在抑制阳光照射的致突变和致癌后果中至关重要，从而减少了人类皮肤癌的发病率。
DNA polymerase η (Polη) is unique among eukaryotic polymerases in its proficient ability for error-free replication through UV induced cyclobutane pyrimidine dimers, and inactivation of Polη in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of yeast Polη 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 efficiently replicate through the UV-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 Gln55, Arg73, and Met74. Together, these features define the basis for Polη's action on UV damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, reducing thereby the incidence of skin cancers in humans.
登录
查看更多内容
影响因子：
64.8
作者：
Nair, DT;Johnson, RE;Aggarwal, AK
通讯作者：
Aggarwal, AK
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
Nair, DT;Johnson, RE;Aggarwal, AK
通讯作者：
Aggarwal, AK
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL