The overexpression of specialized DNA polymerases in cancer
The overexpression of specialized DNA polymerases in cancer
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DOI：
10.1016/j.dnarep.2005.01.005
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发表时间：
2005-05-02
期刊：
影响因子：
3.8
通讯作者：
O'Connor, MJ
中科院分区：
文献类型：
--
作者：
Albertella, MR;Lau, A;O'Connor, MJ
需要特殊的DNA聚合酶来绕过DNA损伤损伤，否则会导致复制停滞和细胞死亡。当在非规范模板上操作时，如未受损的DNA或非同源病变，这些聚合酶表现出相当低的保真度，导致突变的产生。这些聚合酶的异位过表达也会导致突变率的增加和DNA修复能力的增强，这表明如果它们在癌症中过度表达，它们可能会作为致癌基因。在这里，我们检查DNA聚合酶的表达模式在匹配的正常和肿瘤样本从不同的组织范围。除了研究特异性聚合酶beta， lambda， iota和kappa外，我们还研究了复制聚合酶alpha， delta和epsilon的表达。所提供的数据为肿瘤中特异性聚合酶的过表达提供了证据，在68个研究的肿瘤样本中，超过45%的肿瘤样本显示至少一种特异性聚合酶的表达增加了两倍以上。特别值得注意的是，DNA聚合酶β (pol β)在大约三分之一的肿瘤类型的mRNA和蛋白水平上都被发现过表达，在子宫、卵巢、前列腺和胃样本中过表达尤为频繁。Pols lambda和iota也被发现在一系列肿瘤类型中显著过表达，尽管频率低于pol β。相比之下，pol kappa在肿瘤中很少被发现过表达，但在许多样本中被发现普遍低表达。通过siRNA下调pol β表达导致对化疗药物顺铂的敏感性增加，这表明该聚合酶在提供对顺铂诱导损伤的耐受性方面发挥了作用。这些观察结果表明，特殊的DNA聚合酶，特别是pol - β，可以被认为是肿瘤发生过程中改变的看守基因，也是使肿瘤对化疗敏感的潜在药物靶点。(c) 2005 Elsevier B.V.版权所有
Specialized DNA polymerases are required to bypass DNA damage lesions that would otherwise cause replication arrest and cell death. When operating on non-canonical templates, such as undamaged DNA or on non-cognate lesions, these polymerases exhibit considerably reduced fidelity, resulting in the generation of mutations. Ectopic overexpression of these polymerases can also lead to an increased mutation rate and an enhanced capability of DNA repair, suggesting that they could potentially act as oncogenes if they were overexpressed in cancers. Here, we examine expression patterns of DNA polymerases in matched normal and tumor samples from a diverse range of tissues. As well as investigating the specialized polymerases beta, lambda, iota and kappa, we also investigate the expression of the replicative polymerases alpha, delta and epsilon. The data presented provide evidence for the overexpression of specialized polymerases in tumors, with more than 45% of the 68 tumor samples studied demonstrating greater than two-fold enhanced expression of at least one specialized polymerase. Of particular note, DNA polymerase beta (pol beta) was found to be overexpressed at both the mRNA and protein level in approximately one third of all tumor types studied, with overexpression being particularly frequent in uterus, ovary, prostate and stomach samples. Pols lambda, and iota were also found to be overexpressed to a significant extent in a range of tumor types, albeit less frequently than pol beta. In contrast, pol kappa was rarely found to be overexpressed in tumors but was found to be commonly underexpressed in many samples. Downregulation of pol beta expression by siRNA resulted in an increased sensitivity to the chemotherapeutic agent cisplatin, suggesting a role for this polymerase in providing tolerance to cisplatin-induced damage. These observations suggest that specialised DNA polymerases, and particularly pol beta, could be considered both as caretaker genes altered during tumorigenesis, and as potential drug targets to sensitise tumors to chemotherapy. (c) 2005 Elsevier B.V. All rights reserved.