之前的小規(guī)模測序研究已經(jīng)發(fā)現(xiàn),，約30%的不同組織來源的人類腫瘤，其DNA聚合酶β已經(jīng)發(fā)生突變,。
研究表明,，許多這種突變體具有異常的酶催化功能，誘導(dǎo)了細胞性狀轉(zhuǎn)化及基因組的不穩(wěn)定性,，這表明它們與腫瘤發(fā)生發(fā)展息息相關(guān),。
近日，美國耶魯大學(xué)的研究人員Joann B. Sweasy等人發(fā)現(xiàn)，在大部分人類結(jié)直腸腫瘤里,，POLB基因發(fā)生了突變,。相關(guān)研究成果于5月11日發(fā)表在The Journal of Biological Chemistry。
在這項研究里,，利用134例人類結(jié)直腸腫瘤樣本,，他們對POLB基因進行了測序。結(jié)果發(fā)現(xiàn)在40%的樣本中,，POLB基因的編碼區(qū)發(fā)生突變,。
許多Pol β突變體是非同義突變氨基酸置換突變，預(yù)計這影響了聚合酶的正常功能,。
體外實驗發(fā)現(xiàn),，這些DNA聚合酶β突變體酶活性降低，不能充分拯救利用甲基甲烷磺酸(MMS)誘導(dǎo)的聚合酶β缺陷細胞,。
腫瘤細胞含有酶活性降低的突變體,，正如之前的MMS敏感性研究，這很可能影響了堿基切除修復(fù)(BER),。而對BER的破壞可能會通過增加突變生成或是基因組的不穩(wěn)定性,，促進腫瘤發(fā)生。
Joann B. Sweasy表示,，該研究結(jié)果表明腫瘤表達的Polβ突變體可能還會影響基于DNA損傷的治療,。（生物谷Deepblue編譯）
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.
