Interaction between DNA Polymerase λ and Anticancer Nucleoside Analogs
Interaction between DNA Polymerase λ and Anticancer Nucleoside Analogs
复制标题
DOI：
10.1074/jbc.m109.094391
复制
发表时间：
2010-05-28
影响因子：
4.8
通讯作者：
Chou, Kai-ming
中科院分区：
文献类型：
--
作者：
Garcia-Diaz, Miguel;Murray, Michael S.;Chou, Kai-ming
阿糖胞苷（AraC）和吉西他滨（dFdC）的抗癌活性被认为是由于掺入DNA后链终止的结果。为了在原子水平上研究它们与DNA的结合，我们展示了人类DNA聚合酶lambda （Pol lambda）与缺口DNA结合的晶体结构，其中含有AraC或dFdC配对的相反模板dG。这些结构表明AraC和dFdC可以结合在Pol λ的新生碱基对结合口袋内。虽然AraCTP的核糖构象与正常dCTP相似，但dFdCTP的构象却有明显不同。与这些结构一致，Pol lambda有效地合并了AraCTP而不是dFdCTP。这些数据与Pol lambda可能调节AraC的细胞毒性作用的可能性一致。
The anticancer activity of cytarabine (AraC) and gemcitabine (dFdC) is thought to result from chain termination after incorporation into DNA. To investigate their incorporation into DNA at atomic level resolution, we present crystal structures of human DNA polymerase lambda (Pol lambda) bound to gapped DNA and containing either AraC or dFdC paired opposite template dG. These structures reveal that AraC and dFdC can bind within the nascent base pair binding pocket of Pol lambda. Although the conformation of the ribose of AraCTP is similar to that of normal dCTP, the conformation of dFdCTP is significantly different. Consistent with these structures, Pol lambda efficiently incorporates AraCTP but not dFdCTP. The data are consistent with the possibility that Pol lambda could modulate the cytotoxic effect of AraC.