Prostate-cancer-associated 1260M variant of DNA polymerase β is a sequence-specific mutator
Prostate-cancer-associated 1260M variant of DNA polymerase β is a sequence-specific mutator
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DOI：
10.1021/bi051179z
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发表时间：
2005-12-06
期刊：
影响因子：
2.9
通讯作者：
Sweasy, JB
中科院分区：
文献类型：
--
作者：
Dalal, S;Hile, S;Sweasy, JB
研究表明，迄今为止测序的189个肿瘤中有30%表达正常组织中不存在的聚合酶β（pol β）蛋白变体。这增加了pol beta变异体可能与癌症病因相关的可能性。在这里，我们描述了I260M前列腺癌相关的pot β变体。Ile260是疏水铰链的关键残基，其对于聚合酶的关闭是重要的。在这项研究中，我们证明了I260M变异体是一种序列上下文依赖的增变聚合酶。具体地，I260M是二嘧啶序列中错配介导的错误的增变子。I260 M也是一种低保真度聚合酶，在特定序列背景下诱导颠换。我们的研究结果表明，铰链影响的几何形状的DNA聚合酶活性位点内的准确的DNA合成是很重要的。重要的是，I260M变体的表征表明其具有可能与人类癌症的病因学或恶性进展相关的功能表型。
Studies show that 30% of 189 tumors sequenced to date express variants of the polymerase beta (pol beta) protein that are not present in normal tissue. This raises the possibility that variants of pol beta might be linked to the etiology of cancer. Here, we characterize the I260M prostate-cancer-associated variant of pot beta. Ile260 is a key residue of the hydrophobic hinge that is important for the closing of the polymerase. In this Study, we demonstrate that the I260M variant is a sequence context-dependent mutator polymerase. Specifically, I260M is a mutator for misalignment-mediated errors in dipyrimidine sequences. I260M is also a low-fidelity polymerase with regard to the induction of transversions within specific sequence contexts. Our results suggest that the hinge influences the geometry of the DNA within the polymerase active site that is important for accurate DNA synthesis. importantly, characterization of the I260M variant shows that it has a functional phenotype that could be linked to the etiology or malignant progression of human cancer.