Human POLB Gene Is Mutated in High Percentage of Colorectal Tumors
Human POLB Gene Is Mutated in High Percentage of Colorectal Tumors
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DOI：
10.1074/jbc.m111.324947
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发表时间：
2012-07-06
影响因子：
4.8
通讯作者：
Sweasy, Joann B.
中科院分区：
文献类型：
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作者：
Donigan, Katherine A.;Sun, Ka-Wai;Sweasy, Joann B.
之前的小规模测序研究表明，平均 30% 的不同组织来源的人类肿瘤中存在 DNA 聚合酶 β (pol β) 变体。许多这些变体已被证明在体外具有异常的酶功能，并在体内诱导细胞转化和/或基因组不稳定，表明它们的存在与肿瘤发生或其进展有关。在这项研究中，对 134 个人类结直肠肿瘤的人类 POLB 基因进行了测序，发现 40% 的样本中含有编码区突变。这些变体映射到 pol β 蛋白的许多不同位点，并且不聚集。许多变体是非同义氨基酸取代，预计会影响酶功能。这些变体的一个子集被发现在体外具有降低的酶活性，并且未能完全挽救 pol β 缺陷细胞免受甲基甲烷磺酸盐诱导的细胞毒性。正如我们的甲基甲磺酸盐敏感性研究所证明的那样，含有酶活性降低的变异体的肿瘤可能会损害碱基切除修复功能。这种受损的碱基切除修复可能通过导致突变或基因组不稳定性的增加来驱动肿瘤发生。
Previous small scale sequencing studies have indicated that DNA polymerase beta (pol beta) variants are present on average in 30% of human tumors of varying tissue origin. Many of these variants have been shown to have aberrant enzyme function in vitro and to induce cellular transformation and/or genomic instability in vivo, suggesting that their presence is associated with tumorigenesis or its progression. In this study, the human POLB gene was sequenced in a collection of 134 human colorectal tumors and was found to contain coding region mutations in 40% of the samples. The variants map to many different sites of the pol beta protein and are not clustered. Many variants are non-synonymous amino acid substitutions predicted to affect enzyme function. A subset of these variants was found to have reduced enzyme activity in vitro and failed to fully rescue pol beta-deficient cells from methylmethane sulfonate-induced cytotoxicity. Tumors harboring variants with reduced enzyme activity may have compromised base excision repair function, as evidenced by our methylmethane sulfonate sensitivity studies. Such compromised base excision repair may drive tumorigenesis by leading to an increase in mutagenesis or genomic instability.