JBC：DNA聚合酶β突变体能够促进肿瘤发生

之前的小规模测序研究已经发现，约30%的不同组织来源的人类肿瘤，其DNA聚合酶β已经发生突变。

研究表明，许多这种突变体具有异常的酶催化功能，诱导了细胞性状转化及基因组的不稳定性，这表明它们与肿瘤发生发展息息相关。

近日，美国耶鲁大学的研究人员Joann B. Sweasy等人发现，在大部分人类结直肠肿瘤里，POLB基因发生了突变。相关研究成果于5月11日发表在The Journal of Biological Chemistry。

在这项研究里，利用134例人类结直肠肿瘤样本，他们对POLB基因进行了测序。结果发现在40%的样本中，POLB基因的编码区发生突变。

许多Pol β突变体是非同义突变氨基酸置换突变，预计这影响了聚合酶的正常功能。

体外实验发现，这些DNA聚合酶β突变体酶活性降低，不能充分拯救利用甲基甲烷磺酸(MMS)诱导的聚合酶β缺陷细胞。

肿瘤细胞含有酶活性降低的突变体，正如之前的MMS敏感性研究，这很可能影响了碱基切除修复(BER)。而对BER的破坏可能会通过增加突变生成或是基因组的不稳定性，促进肿瘤发生。

Joann B. Sweasy表示，该研究结果表明肿瘤表达的Polβ突变体可能还会影响基于DNA损伤的治疗

doi: 10.1074/jbc.M111.324947
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The Human POLB Gene is Mutated in a High Percentage of Colorectal Tumors

Katherine A. Donigan, Ka-Wai Sun, Antonia A. Nemec, Drew L. Murphy, Xiangyu Cong, Veronika Northrup, Daniel Zelterman and Joann B. Sweasy.

Previous small scale sequencing studies have indicated that DNA Polymerase β 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 mutation(s) in 40% of the samples.The variants map to many different sites of the Pol β protein and are not clustered. Many variants are nonsynonymous 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 β deficient cells from methyl methane sulfonate (MMS) induced cytotoxicity.
Tumors harboring variants with reduced enzyme activity may have compromised base excision repair (BER) function, as evidenced by our MMS sensitivity studies. Such compromised BER may contribute to tumorigenesis by leading to an increase in mutagenesis or genomic instability.Our results also indicate that tumors expressing Pol β variants may exhibit altered responses to DNA damage based therapies.