Human SNM1A - a novel DNA repair role and the development of inhibitors.

我们的基因蓝图包含在细胞核中含有DNA的长染色体复合体中。然而，作为正常细胞功能的副产品，细胞DNA不断受到活性化学物质的攻击，这种损害必须修复。不能准确或及时地修复DNA与许多疾病有关，最突出的是癌症。幸运的是，细胞遭受的DNA损伤可以通过几种复杂的细胞途径修复，从而最大限度地减少我们DNA的变化，从而抑制肿瘤的形成。然而，也许令人惊讶的是，DNA损伤是由许多抗癌治疗（化疗和放疗）引起的，正是这种DNA损伤有效地杀死了癌细胞。在这个提议中，我们的目标是定义一个特定的DNA修复因子，命名为SNM1A，如何修复受损的DNA。我们最近发现SNM1A在DNA双螺旋断裂的修复中起着重要的作用，这是放疗和某些抗癌药物引起的DNA损伤的临床重要形式。我们将定义SNM1A如何在全细胞和纯化的SNM1A蛋白的生化研究中促进这些双链断裂的修复。此外，我们最近在试管中发现了几种可以抑制SNM1A活性的化合物，并致力于将这些化合物开发成可以进入癌细胞并抑制SNM1A的分子。这些将是进一步研究SNM1A的有力工具，也可能最终使我们能够开发SNM1A抑制剂药物，从而改善患者对DNA损伤化疗药物和放疗的反应。

Our genetic blueprint is contained within long, chromosomal complexes containing DNA present in the nucleus of our cells. However, cellular DNA is constantly under attack from reactive chemicals generated as a by-product of normal cellular function, and this damage must be repaired. Failure to repair DNA in an accurate or timely fashion is associated with a number of diseases, most prominently cancer. The DNA damage sustained by cells can, fortunately, be repaired by several complex cellular pathways, minimising changes in our DNA and thereby suppressing tumour formation.Perhaps surprisingly, however, DNA damage is induced by many anticancer treatments (chemotherapy and radiotherapy) and it is this DNA damage that is effective in killing cancer cells. In this proposal we aim to define how a specific DNA repair factor, named SNM1A, acts to repair damaged DNA. We have recently discovered that SNM1A plays an important role in the repair of breaks in the DNA double-helix, which is the clinically important form of DNA damage produced by radiotherapy and certain anticancer drugs. We will define how SNM1A promotes the repair of these double-strand breaks in both whole cells and also in biochemical studies of purified SNM1A protein. Moreover, we have recently identified several chemical compounds that can inhibit SNM1A activity in the test-tube, and aim to develop these into molecules that can enter cancer cells and inhibit SNM1A. These will be very powerful tools for further studies if SNM1A, and also might ultimately allow us to develop SNM1A inhibitor drugs that could improve patients' response to DNA damaging chemotherapy agents and radiotherapy.