Mis-regulation of mRNA poly (A) site selection in cancer cells (PQ11)

描述（由申请人提供）：癌症的一个特征是它是一种基因错误表达的疾病。该应用程序解决了基因表达在癌症中如何被添加多聚(A)尾的mRNA 3'端异常成熟所破坏。大多数人类基因都有多个聚(A)位点，因此，在不同的聚(A)位点之间做出选择几乎是基因表达中普遍存在的事件。在最近其他实验室的突破性工作中，有报道称癌细胞中选择性聚(A)位点的选择通常被破坏。这一点很重要，因为poly(A)位点的选择可以通过决定mRNA的3'非翻译区（UTR）中包含哪些序列来对蛋白质表达产生重大影响。3' UTR序列是microrna和RNA结合蛋白调控mRNA稳定性和翻译效率的主要靶点。例如，如果选择一个聚(a)位点切断这些目标序列以产生一个缩短的3'UTR， mrna就会逃避这些控制。关于癌细胞中哪些基因受到异常多聚(A)位点选择的影响，以及这一过程是否在肿瘤进化过程中受到调控，我们仍然缺乏全面的信息。此外，关于如何选择一个聚(A)位点而不是另一个位点进行加工的基础知之甚少。癌细胞将mRNA 3'端加工从“正确的”聚(A)位点转移的过程可能出了什么问题，这在很大程度上是一个谜。我们建议解决两个广泛的基本问题：1)“在肿瘤进展、对缺氧的适应和对治疗的反应过程中，癌细胞中异常多聚(A)位点选择会影响哪些基因？”2)“癌细胞中mRNA 3'端形成破坏的分子基础是什么？”我们将使用全基因组RNA-seq和ChIP-seq策略，利用人类乳腺癌和肺癌细胞来回答这些问题。

DESCRIPTION (provided by applicant): A hallmark of cancer is that it is a disease of gene misexpression. This application addresses how gene expression in cancer is disrupted by aberrant maturation of mRNA 3' ends where the poly (A) tail is added. Most human genes have multiple poly (A) sites and, as a result, making choices between alternative poly (A) sites is an almost ubiquitous event in gene expression. In recent groundbreaking work by other labs, it was reported that alternative poly (A) site choice is commonly disrupted in cancer cells. This is important because poly(A) site choice can have a large impact on protein expression by dictating what sequences are included in an mRNA's 3' untranslated region (UTR). 3' UTR sequences are the principle targets for microRNAs and RNA binding proteins that regulate mRNA stability and translation efficiency. For example mRNAs will evade these controls if a poly (A) site is chosen that cuts off these target sequences to produce an abbreviated 3'UTR. We still lack comprehensive information about which genes are affected by abnormal poly(A) site selection in cancer cells and whether this process is regulated during tumor evolution. Furthermore little is known about the basis for how one poly(A) site is selected over another for processing. What might be going wrong in cancer cells to divert mRNA 3' end processing from the "correct" poly (A) sites is very much a mystery. We propose to tackle two broad fundamental questions: 1) "What genes are affected by aberrant poly(A) site choice in cancer cells during tumor progression, adaptation to hypoxia, and the response to therapeutics? " and 2) "What is the molecular basis for the corruption of mRNA 3' end formation in cancer cells?". We will use a genome-wide RNA-seq and ChIP-seq strategies to answer these questions using human breast and lung cancer cells.