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NUCKS, a novel double-strand break repair gene, implicated in cancer biology

NUCKS，一种新型双链断裂修复基因，与癌症生物学有关

基本信息

批准号：
9040187
负责人：
Claudia Wiese
金额：
$ 34.48万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-28 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040187
关键词：
1q32.1 Affect BRCA1 gene Biochemical Biological Biological Assay Biological Process Cancer Biology Caseins Cell Death Cell Survival Cells Chemicals Complement Cyclin-Dependent Kinases DNA DNA Binding DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis DNA lesion DNA-Protein Interaction Defect Dependence Diagnosis Disease Double Strand Break Repair Embryo Environmental Risk Factor Excision Exhibits Exposure to Fibroblasts G1 Phase General Population Genes Genetic Recombination Genome Stability Genomic Instability Health Human Human Chromosomes Immune System Diseases Investigation Ionizing radiation Knockout Mice Lead Malignant Neoplasms Medical Mus Mutagens Mutation Neoplasm Metastasis Nerve Degeneration Nuclear Pathway interactions Phenotype Phosphorylation Play Post-Translational Protein Processing Predisposition Premature aging syndrome Prevention Process Proteins Radiation Radiation Tolerance Research Research Design Resistance Risk Role Sequence Homology Testing Tumor Suppression Tumor Suppressor Proteins XRCC3 gene base cancer therapy cancer type chemotherapeutic agent crosslink environmental mutagens homologous recombination human disease improved in vivo interest knock-down malignant breast neoplasm novel overexpression paralogous gene prevent radiation carcinogenesis recombinase recombinational repair repaired research study tumor

项目摘要

DESCRIPTION (provided by applicant): DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can occur spontaneously during DNA replication, but also can be introduced by exposure to ionizing radiation (IR) or to chemical mutagens. DSBs can lead to cell death, mutations and cancer, and defects in DSB repair (DSBR) underlie many human diseases, including disorders associated with cancer predisposition, radiosensitivity, immune dysfunction, neurodegeneration and premature aging. Nuclear Ubiquitous Casein and Cyclin-dependent Kinases Substrate (NUCKS) is a 27 kD, DNA-binding and vertebrate-specific protein with unknown function. NUCKS is abundant in rapidly growing cells and overexpressed in a variety of human cancers. Of particular interest, the NUCKS gene is located on human chromosome 1q32.1, a region that is commonly gained in breast cancer. Based on sequence homology to RAD51 Associated Protein 1 (RAD51AP1), a critical factor in homologous recombination repair (HRR), we have tested and determined a role for NUCKS in DSBR. Our results show that human cells with NUCKS knockdown are hypersensitive to IR and to chemical mutagens, and that NUCKS regulates not only HRR, but also cellular resistance to IR in G1-phase cells. In preliminary experiments using mice with heterozygous Trp53, we find that impaired Nucks function significantly increases the susceptibility to IR-induced tumors, alters the tumor spectrum and promotes metastasis. We now intend to further define how NUCKS regulates DSBR capacity using biochemical and cell-based assays (Aims 1 & 2). In addition, we will carry out a systematic study to further determine the phenotypic consequences of Nucks disruption in mice (Aim 2). Our findings showing a role for NUCKS in DSBR and in preventing radiation carcinogenesis are the first evidence for a biological function of NUCKS, a protein that was discovered more than 25 years ago. Given the importance of DSBR and HRR in tumor suppression and in the removal of DNA lesions induced by IR and other environmental mutagens, the results from our investigation will have direct relevance to risk predictions for health from environmental factors. In addition, our studies may also contribute to the improved diagnosis, prevention and treatment of cancer.

描述(申请人提供)：DNA双链断裂(DSB)是一种剧毒的DNA损伤，可在DNA复制过程中自发发生，但也可通过暴露于电离辐射(IR)或化学诱变剂而引入。DSB可导致细胞死亡、突变和癌症，DSB修复缺陷(DSBR)是许多人类疾病的基础，包括与癌症易感性、辐射敏感性、免疫功能障碍、神经退化和过早衰老相关的疾病。核泛在酪蛋白和细胞周期蛋白依赖蛋白底物(NUCKS)是一种27kD的DNA结合蛋白，是脊椎动物特有的蛋白，功能未知。NUCKS在快速生长的细胞中大量存在，并在多种人类癌症中过度表达。特别有趣的是，NUCKS基因位于人类染色体1q32.1上，这是乳腺癌中常见的一个区域。基于与同源重组修复(HRR)中的关键因子RAD51相关蛋白1(RAD51AP1)的序列同源性，我们测试并确定了NUCKS在DSBR中的作用。我们的结果表明，NUCKS基因敲除的人细胞对IR和化学诱变剂高度敏感，并且NUCKS不仅调节细胞的HRR，而且还调节G1期细胞对IR的抵抗。在使用TrP53杂合子的小鼠的初步实验中，我们发现Nucks功能受损显著增加了对IR诱导的肿瘤的敏感性，改变了肿瘤光谱并促进了转移。我们现在打算进一步定义NUCKS如何使用生化和基于细胞的分析来调节DSBR能力(目标1和2)。此外，我们将开展一项系统研究，以进一步确定Nucks干扰在小鼠中的表型后果(目标2)。我们的发现显示了NUCKS在DSBR和预防辐射致癌中的作用，这是NUCKS生物学功能的第一个证据，NUCKS是一种在25年前发现的蛋白质。鉴于DSBR和HRR在抑制肿瘤和清除IR和其他环境诱变剂引起的DNA损伤方面的重要性，我们的研究结果将与环境因素对健康的风险预测直接相关。此外，我们的研究还可能有助于改善癌症的诊断、预防和治疗。