DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis.
DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis.
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DOI：
10.7554/elife.00534
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发表时间：
2013-04-16
期刊：
影响因子：
7.7
通讯作者：
Neuberger MS
中科院分区：
文献类型：
--
作者：
Taylor BJ;Nik-Zainal S;Wu YL;Stebbings LA;Raine K;Campbell PJ;Rada C;Stratton MR;Neuberger MS
乳腺癌基因组揭示了一种新形式的突变簇射（kataegis），其中间隔一到几百个核苷酸的C：G对的多个同链取代聚集在DNA酶大小的区域上，通常与DNA重排位点相关。我们发现kataegis可能是由AID/APOBEC催化的DNA断裂附近的胞苷脱氨基作用引起的，可能是通过对切除过程中暴露的单链DNA的作用。癌症样kataegis可以通过在酵母中表达AID/APOBEC家族脱氨酶来重现，其中它在很大程度上依赖于尿嘧啶切除，这产生了链断裂的脱碱基位点。局部kataegis也可以通过I-SceI诱导的断裂而成核。酵母中APOBEC 3催化脱氨的全基因组模式揭示了APOBEC 3B和3A作为脱氨酶，其突变特征与乳腺癌kataegic突变的突变特征最相似。结合表达和功能测定，结果表明APOBEC 3B/A与乳腺癌超突变有关，并深入了解了kataegis的机制。DOI：http://dx.doi.org/10.7554/eLife.00534.001癌细胞的基因组含有正常细胞中不存在的突变。其中一些阻止细胞修复它们的DNA，而另一些则通过导致细胞不受控制地繁殖而引起肿瘤。此外，乳腺癌细胞中的一些突变是成簇发生的，这种现象被称为kataegis（来自希腊语，意为“雷暴”）。Kataegic突变几乎只发生在一个胞嘧啶，前面是一个胸腺嘧啶。这表明，一个被称为AID/APOBEC酶的蛋白质家族--从胞嘧啶中去除胺基--可能参与了这些突变的产生。在这项研究中，Taylor等人证实了这一可能性，表明在酵母细胞中表达AID/APOBEC家族酶的单个成员会增加突变频率并诱导kataegis。由AID/APOBEC酶触发的kataegis可以通过将双链断裂引入DNA中来定位：Taylor等人认为这可能发生，因为修复断裂暴露了单链DNA，然后AID/APOBEC酶对其起作用。通过比较酵母细胞中诱导的突变与乳腺癌细胞中观察到的突变，Taylor等人确定APOBEC 3B是最有可能导致乳腺癌中kataegis的酶（APOBEC 3A在某些癌症中也是一个强有力的候选者）。此外，他们发现APOBEC 3B在乳腺癌细胞系中高度表达，APOBEC 3B和APOBEC 3A也会导致人类细胞的DNA损伤。总的来说，这些发现为kataegis的产生机制提供了关键的见解，并确定了两种可能导致乳腺癌突变的蛋白质。现在需要进一步的工作来确定这些酶是否也会引起其他形式癌症的突变。DOI：http://dx.doi.org/10.7554/eLife.00534.002网站
Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. DOI: http://dx.doi.org/10.7554/eLife.00534.001 The genomes of cancer cells contain mutations that are not present in normal cells. Some of these prevent cells from repairing their DNA, while others give rise to tumours by causing cells to multiply uncontrollably. Moreover, some of the mutations in breast cancer cells occur in clusters—a phenomenon known as kataegis (from the Greek for ‘thunderstorm’). Kataegic mutations occur almost exclusively at a cytosine preceded by a thymine. This suggests that a family of proteins called AID/APOBEC enzymes—which remove amine groups from cytosines—may be involved in generating these mutations. In this study, Taylor et al. confirm this possibility by showing that expressing individual members of the AID/APOBEC family of enzymes in yeast cells increases the mutation frequency and induces kataegis. The kataegis triggered by the AID/APOBEC enzymes could be localised through the introduction of double-stranded breaks into the DNA: Taylor et al. suggest that this might happen because repairing the breaks exposes single-stranded DNA, which the AID/APOBEC enzymes then act upon. By comparing the mutations induced in the yeast cells with those observed in breast cancer cells, Taylor et al. identified APOBEC3B as the enzyme most likely to be responsible for kataegis in breast cancer (with APOBEC3A also a strong candidate in some cancers). Moreover, they showed that APOBEC3B was highly expressed in breast cancer cell lines, and that APOBEC3B and APOBEC3A can also cause DNA damage in human cells. Taken together, the findings provide key insights into the mechanism by which kataegis arises, and identify two proteins likely to contribute to the mutations seen in breast cancer. Further work is now required to determine whether these enzymes also give rise to mutations in other forms of cancer. DOI: http://dx.doi.org/10.7554/eLife.00534.002