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

人类 SNM1A - 一种新型 DNA 修复作用抑制剂的开发。

• 批准号: MR/L007665/1
• 负责人: Peter McHugh
• 金额: $ 89.92万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL007665%2F1
• 关键词: Human; SNM1A; novel; DNA; repair

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.

我们的基因蓝图包含在长而长的染色体复合体中，这些复合体含有存在于我们细胞细胞核中的DNA。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，这种损伤必须修复。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进行修复，最大限度地减少DNA的变化，从而抑制肿瘤的形成。然而，令人惊讶的是，许多抗癌治疗(化疗和放射治疗)都会引起DNA损伤，正是这种DNA损伤才能有效地杀死癌细胞。在这项提案中，我们的目标是定义一种名为SNM1A的特定DNA修复因子如何修复受损的DNA。我们最近发现SNM1a在DNA双螺旋断裂的修复中起重要作用，双螺旋DNA是放射治疗和某些抗癌药物造成的DNA损伤的临床重要形式。我们将确定SNM1A如何促进这些双链断裂在整个细胞中的修复，以及在纯化的SNM1A蛋白的生化研究中。此外，我们最近发现了几种化合物，可以在试管中抑制SNM1A的活性，目标是将这些化合物开发成能够进入癌细胞并抑制SNM1A的分子。这些都将是进一步研究SNM1A的非常强大的工具，也可能最终使我们能够开发SNM1A抑制剂药物，可以改善患者对破坏DNA的化疗药物和放射治疗的反应。

项目成果

The SNM1A DNA repair nuclease.

• DOI: 10.1016/j.dnarep.2020.102941
• 发表时间: 2020-11
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Baddock HT;Yosaatmadja Y;Newman JA;Schofield CJ;Gileadi O;McHugh PJ
• 通讯作者: McHugh PJ

RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks.

• DOI: 10.15252/embj.201796664
• 发表时间: 2017-07-14
• 期刊: The EMBO journal
• 作者: Abdullah UB;McGouran JF;Brolih S;Ptchelkine D;El-Sagheer AH;Brown T;McHugh PJ
• 通讯作者: McHugh PJ

The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities.

• DOI: 10.1093/nar/gkv1256
• 发表时间: 2015-12-15
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Allerston CK;Lee SY;Newman JA;Schofield CJ;McHugh PJ;Gileadi O
• 通讯作者: Gileadi O