FEN1精氨酸去甲基化调控基因组稳定性及肿瘤发生的分子机制研究

FEN1是一种结构特异性核酸内切酶，在DNA复制和修复中起着重要的作用。FEN1功能失调将导致基因组不稳定，诱导肿瘤的发生。因此，阐明FEN1的调控机制，具有重要的意义。在前期的工作中，我们发现精氨酸甲基化修饰是FEN1功能调控的重要方式。FEN1精氨酸甲基化水平与细胞基因组稳定性有着密切的关系。我们业已经阐明FEN1的精氨酸甲基化机制，然而对其逆过程---精氨酸去甲基化是如何发生的？仍一无所知。近来，我们发现了一个潜在的FEN1精氨酸去甲基化酶，命名为RDM1。预实验结果表明RDM1可以在体内外特异性地去除FEN1的精氨酸甲基化修饰。在本项目中，我们将围绕RDM1，深入地阐明其对FEN1精氨酸甲基化水平的调控作用及对基因组稳定性的影响，并利用转基因小鼠研究其在肿瘤发生和发展中的作用机制。本项目将促进对蛋白质精氨酸去甲基化机制的研究，丰富基因组稳定性和表观遗传学调控理论。

It has been reported that genomic instability is associated with the cancer onset and development. Knowledge on mechanisms by which genomic stability is maintained, particularly those by which DNA damage is repaired, will benefit greatly to cancer prevention, treatment and anti-cancer drug development. Using DNA repair protein FEN1 as a research model, we have revealed the complexity of molecular events of genomic instability induced cancer initiation and published research papers on top journals such as Molecular Cell and Nature Chemical Biology. In previous studies, we have identified protein arginine methylation as a key regulator for FEN1 function and DNA repair efficiency. Importantly, we observed the dynamic change of FEN1 arginine methylation and speculated the existence of arginine demethylase in cells. Up to now, we have identified the first non-histone protein arginine demethylase. In the current proposal, we focus on the studies of biochemical characters and biological significance of FEN1 demethylase, in aiming to undercover the relationship between genomic instability and cancer onset and development.