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

蛋白质的合成对于任何已知的生命形式都是绝对必要的。它是由一种叫做核糖体的细胞器完成的，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）是核糖体的关键组成部分，rRNA对其结构和功能都至关重要。rRNA的合成（也称为转录）是核糖体产生的关键调节因子，也是生命的基础。核糖体RNA的转录与细胞的生长和分裂紧密相关，并且当失调时可能对细胞的命运产生巨大影响，导致细胞死亡或可能导致致癌转化的缺陷。rRNA合成水平的提高支持癌细胞的无限制增殖，因此rRNA转录是抗癌治疗的有效靶点。在拟议的研究中，我们将使用各种生物化学方法来研究rRNA转录的机制，并将重点关注拓扑异构酶-II，最令人惊讶的酶之一，在调节人类细胞中rRNA转录中的作用。拓扑异构酶是DNA世界的魔法师，是许多非常成功的抗癌药物的靶点，也是开发更好治疗方法的关键靶点。因此，拟议的研究将把两个高度关注和重要的领域结合起来，并将有助于开发新一代药物，针对与过度增殖和异常细胞大小相关的疾病，包括癌症和心脏病。此外，选择性靶向细胞中rRNA合成的药物可用于刺激细胞替代治疗策略中的细胞生长和增殖，以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.