文章：

DNA聚合酶和癌症

DNA polymerases and cancer

原文发布日期：2011-01-24

DOI: 10.1038/nrc2998

类型: Review Article

开放获取: 否

要点：

1. Fifteen DNA polymerases are encoded in mammalian genomes. Some function in the replication of the genome, but most participate in specialized DNA repair and DNA damage tolerance processes. The activity of these DNA polymerases will affect the response of a cell to DNA-damaging carcinogens and chemotherapeutic agents.
2. Some DNA polymerases catalyse DNA synthesis on damaged sites in DNA, helping cells tolerate DNA damage by translesion DNA synthesis (TLS). TLS polymerases are specialized for the bypass of different DNA adducts. Defects in Pol η (also known as POLH) are responsible for the variant type of xeroderma pigmentosum (XP-V).
3. Pol ζ (the catalytic subunit of which is REV3L) and REV1 are required for nearly all damage-induced base change mutagenesis in mammalian cells. Reduction of their activities sensitizes cells, including tumour cells, to DNA-damaging agents. However, chromosome rearrangements and inflammation can increase in the absence of these proteins, promoting carcinogenesis.
4. The expression of some genes encoding DNA polymerases may be altered in some cancers. In breast cancers, levels of POLQ (which encodes Pol θ) seem to be the most elevated compared with normal levels of expression. Comprehensive studies of DNA polymerase protein levels in cancer remain to be carried out.
5. The inhibition of DNA polymerase activities could be useful as an adjuvant to DNA-damaging therapies, and inhibitors for some polymerases have been found. Pharmacologically effective inhibitors highly specific for a single DNA polymerase remain to be identified.
6. Whole-genome analyses of cancers have not yet revealed cancer-associated alterations in DNA polymerase genes. It seems likely, however, that at least some cells in a tumour will have relevant alterations. Some DNA polymerases can be considered as tumour suppressors (Pol ζ, REV1, Pol η, Pol ι, Pol κ, Pol δ and Pol ɛ).

要点翻译：

1. 哺乳动物基因组编码十五种DNA聚合酶。其中一些参与基因组的复制，但大多数参与专门的DNA修复和DNA损伤耐受过程。这些DNA聚合酶的活性会影响细胞对DNA损伤性致癌物和化疗药物的反应。
2. 某些DNA聚合酶能催化DNA损伤位点的合成，通过跨损伤DNA合成帮助细胞耐受DNA损伤。跨损伤DNA聚合酶专门用于绕过不同的DNA加合物。Pol η（亦称POLH）缺陷是导致着色性干皮病变异型的原因。
3. Pol ζ（其催化亚基为REV3L）和REV1几乎是哺乳动物细胞中所有损伤诱导碱基改变诱变所必需的。降低其活性会使细胞（包括肿瘤细胞）对DNA损伤剂更敏感。然而，缺乏这些蛋白可能增加染色体重排和炎症，从而促进癌变。
4. 在某些癌症中，编码DNA聚合酶的基因表达可能发生改变。在乳腺癌中，POLQ（编码Pol θ）的表达水平相较于正常表达水平似乎升高最为显著。关于癌症中DNA聚合酶蛋白水平的全面研究仍有待开展。
5. 抑制DNA聚合酶活性可能作为DNA损伤疗法的有效辅助手段，目前已发现针对某些聚合酶的抑制剂。针对单一DNA聚合酶的高特异性药理学有效抑制剂仍有待开发。
6. 癌症全基因组分析尚未揭示DNA聚合酶基因中与癌症相关的改变。然而，肿瘤中至少部分细胞很可能存在相关改变。某些DNA聚合酶可被视为肿瘤抑制因子（Pol ζ、REV1、Pol η、Pol ι、Pol κ、Pol δ和Pol ɛ）。

英文摘要：

There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, the ability of some of these enzymes to bypass DNA damage may actually defend against chromosome instability in cells, and at least one DNA polymerase, Pol ζ, is a suppressor of spontaneous tumorigenesis. Because DNA polymerases can help cancer cells tolerate DNA damage, some of these enzymes might be viable targets for therapeutic strategies.

摘要翻译： 

哺乳动物基因组编码有15种不同的DNA聚合酶，它们分别专精于复制、修复或耐受DNA损伤。新的证据正在揭示DNA聚合酶在损伤特异性和组织特异性中的功能。癌细胞中出现的许多点突变源于DNA聚合酶产生错误的能力。然而，其中一些酶绕过DNA损伤的能力实际上可能有助于防御细胞中的染色体不稳定性，并且至少有一种DNA聚合酶，即Pol ζ，是自发肿瘤发生的抑制因子。由于DNA聚合酶可以帮助癌细胞耐受DNA损伤，因此其中一些酶可能成为治疗策略的可行靶点。

原文链接：

DNA polymerases and cancer