Signatures of selection in fusion transcripts resulting from chromosomal translocations in human cancer.
Signatures of selection in fusion transcripts resulting from chromosomal translocations in human cancer.
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DOI：
10.1371/journal.pone.0004805
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Novo FJ
中科院分区：
文献类型：
--
作者：
Ortiz de Mendíbil I;Vizmanos JL;Novo FJ
人类肿瘤中易位断裂点的复发和非随机分布通常归因于断裂点附近存在的局部序列特征。然而，也有人认为，功能限制可能有助于划定易位断点的位置内的基因参与，但这种贡献的定量分析一直缺乏。我们已经分析了两个众所周知的功能选择的签名，如阅读框的兼容性和蛋白质结构域的非随机组合，在一个广泛的数据集上的融合蛋白在癌症中的染色体易位。我们的数据提供了强有力的实验支持的概念，易位断裂点的位置在基因组中的癌细胞是确定的，在很大程度上，通过需要联合收割机某些蛋白质结构域，并保持一个完整的阅读框架的融合转录。此外，我们收集的信息提供了一个整体的观点，致癌机制和结构域的结构，融合蛋白。这可用于评估新的染色体易位的功能影响，并预测所涉及的基因中断点的位置。
The recurrence and non-random distribution of translocation breakpoints in human tumors are usually attributed to local sequence features present in the vicinity of the breakpoints. However, it has also been suggested that functional constraints might contribute to delimit the position of translocation breakpoints within the genes involved, but a quantitative analysis of such contribution has been lacking. We have analyzed two well-known signatures of functional selection, such as reading-frame compatibility and non-random combinations of protein domains, on an extensive dataset of fusion proteins resulting from chromosomal translocations in cancer. Our data provide strong experimental support for the concept that the position of translocation breakpoints in the genome of cancer cells is determined, to a large extent, by the need to combine certain protein domains and to keep an intact reading frame in fusion transcripts. Additionally, the information that we have assembled affords a global view of the oncogenic mechanisms and domain architectures that are used by fusion proteins. This can be used to assess the functional impact of novel chromosomal translocations and to predict the position of breakpoints in the genes involved.