Exploring how arginine methylation impacts on DNA repair.

基因组不断受到外源性和内源性应激的挑战，这些应激诱导DNA损伤，这些损伤必须被修复以维持基因组稳定性。不能这样做会导致诱变事件，使个体易患许多病理状况，包括癌症和神经功能障碍。通过翻译后修饰对蛋白质功能的动态调节是DNA损伤反应的非常重要的调节剂。虽然这在蛋白质磷酸化和泛素化中越来越受到重视，但最近发现的其他不太清楚的修饰也同样重要。其中一种修饰是精氨酸残基的甲基化，虽然这种修饰在40多年前就被认识到，但直到最近才发现催化这些反应的酶，PRMT，我们开始了解精氨酸甲基化对DNA损伤反应的重要性。探索这一点的一种方法是通过鉴定新的底物。最近，我的实验室已经将PRMT 5描述为DNA损伤应答的必要组分，并且通过RUVBL 1的甲基化修复双链断裂（Clarke et al.，Molecular Cell，2017）。然而，由于不同类型的DNA损伤需要不同的修复途径，因此PRMT5极有可能以DNA损伤依赖的方式甲基化其他底物，或者组蛋白本身受到修饰。本博士项目将进一步探索精氨酸甲基化如何影响DNA修复过程。对于精氨酸甲基化领域来说，这是一个非常令人兴奋的时刻，因为靶向特定PRMT的小分子化合物正在开发中。因此，更好地了解DNA损伤反应期间的PRMT可能会发现治疗癌症或神经系统疾病的新策略。

The genome is constantly being challenged with exogenous and endogenous stresses that induce DNA lesions that must be repaired to maintain genomic stability. An inability to do so leads to mutagenic events that predispose individuals to numerous pathological conditions, including cancer and neurological dysfunction. Dynamic regulation of protein function via post-translational modifications is an incredibly importantly regulator of the DNA damage response. Whilst this has been increasingly appreciated for protein phosphorylation and ubiquitination, other less-well characterised modifications have recently been shown to be equally important.One such modification is the methylation of arginine residues, and whilst this modification was recognised more than 40 years ago, it is only with the recent identification of the enzymes that catalyse these reactions, PRMTs, that we are starting to understand the significance of arginine methylation for the DNA damage response. One way in which to explore this is through the identification of novel substrates. Recently, my laboratory has described PRMT5 as an essential component of the DNA damage response and the repair of double strand breaks through the methylation of RUVBL1 (Clarke et al., Molecular Cell, 2017). However, because different types of DNA damage require distinct pathways for repair, it is highly likely that PRMT5 is methylating other substrates in a DNA damage-dependent manner, or that histones themselves are subjected to modification.This PhD project will further explore how arginine methylation impacts on the DNA repair process. This is a very exciting time for the field of arginine methylation as small molecular compounds that target specific PRMTs are in development. Hence, a better understanding of PRMTs during the DNA damage response may discover novel strategies in which to treat cancer or neurological disease.