Defining the role of ADP-ribosyltransferases in DNA repair and genome stability

通过修复受损的DNA来保持遗传物质的完整性对生物体的健康至关重要。我的实验室专注于了解这些过程，特别是一组名为ADP-核糖基转移酶(ARTS)的酶如何调节各种DNA修复过程。ARTS最明确的作用是促进DNA双链螺旋断裂的修复。使用小分子ART抑制剂(ARTI)抑制这一途径正在临床上被用来特异性地杀死在DNA修复过程中存在缺陷的肿瘤，这种过程称为同源重组。然而，细胞中有几种不同类型的ART，一个新兴的主题是这些酶可以调节不同的DNA修复过程。拟议的工作将建立在我们最近令人兴奋的新发现的基础上，解决不同的ART如何共同作用于修复DNA损伤，以及在暴露于导致DNA损伤的制剂后，抑制一种ART如何更有效地杀死细胞。考虑到目前可用的ARTI靶向多种ART，这些研究将为开发更具特异性的ARTI提供信息，从而提高临床疗效。我们还将定义当与ART一起抑制时会夸大或挽救细胞对DNA损伤的敏感性的新因素，确定使ART抑制的细胞对放射或化疗更敏感或更耐受的途径。这项工作将有助于提高这些药物在临床上的疗效，并确定其抑制作用将克服耐药性的新靶点。

Preserving the integrity of genetic material through repair of damaged DNA is critical for the health of an organism. My laboratory is focussed on understanding these processes, with specific reference to how a set of enzymes called ADP-ribosyltransferases (ARTs) regulate a variety of DNA repair processes.The best defined role of ARTs is in promoting repair of breaks in the DNA double strand helix. Inhibition of this pathway using small molecule ART inhibitors (ARTi) is being exploited in the clinic to specifically kill tumours with defects in a DNA repair process known as homologous recombination. However, there are several different types of ART in a cell and an emerging theme is that these enzymes can regulate different DNA repair processes. The proposed work will build on our recent exciting new findings addressing how different ARTs function together to repair DNA damage and how inhibiting one ART over others more effectively kills cells following exposure to agents that induce DNA damage. Given currently available ARTi target multiple ARTs, these studies will provide information that underpins the development of more specific ARTi with increased efficacy in the clinic. We will also define novel factors that when inhibited along with ARTs either exaggerate or rescue the sensitivity of cells to DNA damage, identifying pathways that make ART inhibited cells more sensitive or tolerant to radio- or chemotherapy. This work will lead to efforts in improving the efficacy of these agents in the clinic and identify new targets whose inhibition will overcome drug resistance.