The role of Topoisomerase II-alpha in regulated transcription of human ribosomal RNA genes

蛋白质的合成对任何已知的生命形式都是绝对必要的。它是由名为核糖体的细胞器执行的，核糖体是最不可思议的细胞机器之一，通常被称为蛋白质工厂。核糖体RNA(RRNA)是核糖体的关键构件，rRNA对核糖体的结构和功能都是必不可少的。RRNA的合成(也称为转录)是核糖体生产的关键调节因子，也是生命的基础。核糖体核糖核酸的转录与细胞的生长和分裂密切相关，当解除调控时，可能会对细胞S的命运产生重大影响，导致细胞死亡或缺陷，从而可能导致致癌转化。RRNA合成水平的提高支持癌细胞的不受抑制的增殖，因此rRNA转录是抗癌治疗的有效靶点。在拟议的研究中，我们将使用各种生化方法来研究rRNA转录的机制，并将重点放在拓扑异构酶-II，最令人惊讶的酶之一，在调节人类细胞rRNA转录中的作用。拓扑异构酶，这些DNA世界的魔术师，是许多非常成功的抗癌药物的靶标，也是开发更好疗法的关键靶点。因此，拟议的研究将把两个高度感兴趣和重要的领域结合在一起，并将有助于开发新一代药物，针对与细胞过度增殖和细胞大小异常相关的疾病，包括癌症和心脏病。此外，在细胞替代治疗策略中，选择性靶向细胞rRNA合成的药物可以用于刺激细胞生长和增殖，从而使退行性细胞疾病患者受益。

Synthesis of proteins is absolutely essential for any known form of life. It is carried out by cellular organelles named ribosomes, one of the most incredible cellular machines, frequently referred to as protein factories. The ribosomal RNA (rRNA) is the key building block of the ribosomes and rRNA is essential to both their structure and function. The synthesis of rRNA (also known as transcription) is the key regulator of ribosome production and fundamental to life. The transcription of ribosomal RNA is tightly linked to cell growth and division and when deregulated could have a dramatic effect on the cell s fate, leading to cell death or defects which might result in oncogenic transformation. An elevated level of rRNA synthesis supports the unrestrained proliferation of cancer cells and rRNA transcription therefore represents a valid target for anticancer therapy.In the proposed research, we will use various biochemical approaches to study the mechanism of rRNA transcription and will focus on the role of topoisomerase-II, one of the most amazing enzymes, in the regulation of rRNA transcription in human cells. Topoisomerases, these magicians of DNA world are targets for a number of highly successful anticancer drugs and a key target for development of better therapeutics.The proposed research would therefore bring together two areas of high interest and importance and will contribute to the development of a new generation of drugs, targeting diseases associated with hyperproliferation and abnormal cell size including cancer and heart diseases. Moreover, drugs selectively targeting rRNA synthesis in cells could be used for stimulation of cell growth and proliferation in cell-replacement therapy strategies to the benefit of those with degenerative cell diseases.