Exploring how arginine methylation impacts on DNA repair.

基因组不断受到外源和内源压力的挑战，导致DNA损伤，必须修复这些损伤才能维持基因组的稳定。无法做到这一点会导致突变事件，使个人容易患上许多病理疾病，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损伤反应的一个极其重要的调节因素。虽然这在蛋白质磷酸化和泛素化方面越来越受到重视，但其他不太典型的修饰最近被证明是同样重要的。其中一种修饰是精氨酸残基的甲基化，虽然这种修饰在40多年前就被认识到了，但直到最近催化这些反应的酶PRMT的发现，我们才开始理解精氨酸甲基化对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，我的实验室将PRMT5描述为DNA损伤反应和通过RUVBL1甲基化的双链断裂修复的重要组成部分(Clarke等人，分子细胞，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很可能以依赖于DNA损伤的方式对其他底物进行甲基化，或者组蛋白本身受到修饰。这个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，因为针对特定PRMT的小分子化合物正在开发中。因此，更好地了解DNA损伤反应过程中的PRMT可能会发现治疗癌症或神经疾病的新策略。

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.