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Characterisation of DNA-Protein Crosslink Repair, a novel DNA repair pathway for protection from accelerated ageing and cancer

DNA-蛋白质交联修复的表征，一种新型 DNA 修复途径，可防止加速衰老和癌症

基本信息

批准号：
1963040
负责人：
金额：
--
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1963040
关键词：
Characterisation DNA Protein Crosslink Repair

项目摘要

DNA-protein crosslinks (DPCs) are under-investigated DNA lesions caused by the covalent attachment of proteins to DNA. DPCs are induced by various endogenous chemicals like aldehydes or by chemotherapeutic drugs. Little is known about how cells repair DPCs and thus acquire resistance to DPC-induced chemotherapy. However, the persistence of DPCs causes genomic instability and cancer. We recently discovered a human syndrome (Ruijs-Aalfs or SPARTAN syndrome) related to the defective DPC repair pathway. SPARTAN syndrome is caused by biallelic and monogenic mutations in SPARTAN gene/protein, and is characterised by genomic instability, premature ageing and liver cancer in children (Lessel et al. Nature Genetics 2014). We demonstrated that SPARTAN is a DNA-dependent metalloprotease, which enzymatically (by its metalloprotease activity) removes covalently attached proteins from DNA (Vaz et al. Molecular Cell, 2016). Altogether, our results demonstrate that we have discovered a novel and specialised DNA repair pathway, namely DNA-protein crosslink proteolysis repair pathway that protects humans from cancer and accelerated ageing (Vaz et al., TIBS, 2017). DPhil project aims to delineate this new DNA-protein crosslink repair pathway by using standard biochemical and cell biological techniques coupled to the state of the art technologies such as Crisper/Cas9 gene editing, mass-spectrometry and super-resolutions microscopy.

DNA-蛋白质交联（DPC）是研究不足的DNA损伤所造成的共价连接的蛋白质到DNA。DPC是由各种内源性化学物质如醛类或化疗药物诱导的。关于细胞如何修复DPC并因此获得对DPC诱导的化疗的抗性知之甚少。然而，DPC的持续存在会导致基因组不稳定和癌症。我们最近发现了一种与DPC修复途径缺陷相关的人类综合征（Ruijs-Aalfs或SPARTAN综合征）。SPARTAN综合征是由SPARTAN基因/蛋白质中的双等位基因和单基因突变引起的，其特征在于基因组不稳定性、过早衰老和儿童肝癌（Lessel et al. Nature Genetics 2014）。我们证明了SPARTAN是一种DNA依赖性金属蛋白酶，它可以酶促（通过其金属蛋白酶活性）从DNA中去除共价连接的蛋白质（Vaz et al. Molecular Cell，2016）。总之，我们的结果表明，我们已经发现了一种新的和专门的DNA修复途径，即DNA-蛋白质交联蛋白水解修复途径，其保护人类免受癌症和加速衰老的影响（Vaz等人，TIBS，2017）。DPhil项目旨在通过使用标准的生物化学和细胞生物学技术，结合最先进的技术，如Criminal/Cas9基因编辑，质谱和超分辨率显微镜，描绘这种新的DNA-蛋白质交联修复途径。