Studies of Lymphoma Suppression and DNA Repair

淋巴瘤抑制和 DNA 修复的研究

• 批准号: 9031726
• 负责人: CHUNYING DU
• 金额: $ 32.58万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031726
• 关键词: Affect; Apoptosis; Binding; Cell division; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Chromosomal translocation; Chromosome abnormality; Complex; Cytokinesis; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA lesion; Data; Development; Disease; Double Strand Break Repair; Embryonic Development; Environmental Health; Enzymes; Etiology; Event; Gene Expression; Genetic; Genetic Recombination; Genome Stability; Genomic DNA; Genomic Instability; Goals; Health; Health Hazards; Human; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Inhibition of Apoptosis; Intervention; Ionizing radiation; J segment gene; Knowledge; Lead; Lesion; Ligase; Lymphatic System; Lymphocyte; Lymphoid; Lymphoma; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mediator of activation protein; Minerals; Mission; Molecular; Mus; Mutant Strains Mice; Mutate; NBS1 gene; Nature; Nonhomologous DNA End Joining; Pathology; Pathway interactions; Patients; Play; Post-Translational Protein Processing; Process; Proteins; Public Health; Rad51 recombinase; Radiation Induced DNA Damage; Recruitment Activity; Regulatory Pathway; Relaxation; Research; Role; Sampling; Signaling Protein; Site; Small Interfering RNA; System; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Microarray; Tumor Suppression; Ubiquitin; Ubiquitin-Conjugating Enzymes; United States; V(D)J Recombination; Work; ataxia telangiectasia mutated protein; base; chromatin modification; gamma-Glutamyl Hydrolase; genetic regulatory protein; homologous recombination; improved; innovation; killings; man; mutant; novel; programs; repaired; sensor; targeted treatment; tumor progression; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Ionizing radiation (IR), produced by certain minerals in the Earth, represents a major environmental health hazard to man because it causes DNA double-strand breaks (DSBs), highly toxic DNA lesions that often result in genome instability and cancer. It is well established that chromosomal translocations at DSBs can promote lymphoma development. However, there still remains a significant gap in the knowledge of regulatory mechanisms of the repair DNA DSBs induced by IR and lymphoma suppression. The BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) is a conserved protein with chimeric ubiquitin-protein conjugase (E2) and ligase (E3) activities that catalyze post-translational modification of proteins by ubiquitin. Until recently, BRUCE has only been shown to be involved in apoptosis inhibition, cytokinesis, and mouse embryogenesis. Recently, our preliminary studies provide the first indication that BRUCE is a suppressor of lymphoma and a regulatory protein in DNA-repair pathways. In particular, we observed that BRUCE mice are susceptible to lymphomas, and that cells with BRUCE inactivated display genomic instabilities and unrepaired DSBs following ionizing radiation. We also observed that BRUCE acts at a step upstream in DNA-repair cascade by regulating the accumulation, at the site of the DSB, of early DNA-damage signaling proteins and downstream repair proteins following IR. Furthermore, BRUCE has strong relevance to human health in that a reduction in the level of BRUCE gene expression is associated with human lymphomas and also correlates with low survival of lymphoma patients. Based on these findings, we hypothesize that BRUCE suppresses chromosomal abnormalities and lymphomagenesis by promoting DNA DSB repair. We propose two aims to test this hypothesis: (1) To determine chromosomal translocations in lymphomas developed in our heterozygous BRUCEWT/C mutant mice, and whether they are resulted from compromised repair of programmed and/or general DSBs in lymphocytes. We will also determine whether reduced levels of BRUCE protein are associated with lymphoma development by analyzing human lymphoma tissue array. (2) To determine the mechanism by which BRUCE regulates access of repair proteins to the sites of DSB and its implication in DSB-repair pathways of homologous recombination (HR) and non-homologous end joining (NHEJ, both classic and alternative). This proposed work is significant because it will be the first indication that BRUCE is a suppressor of lymphoma and a regulatory protein in DNA repair. This work is also innovative because it has never been expected or even speculated that BRUCE, an anti-apoptosis protein, could regulate DNA repair and tumor suppression. It challenges the current ubiquitin paradigm by placing BRUCE upstream of the current ubiquitin regulatory pathway. These results are expected to lay the groundwork for developing novel agents capable of modulating the level and/or the activity of BRUCE for innovative intervention of lymphoma other related diseases resulting from faulty DNA repair.

描述（由申请人提供）：电离辐射（IR）由地球上的某些矿物产生，对人类的环境健康构成重大危害，因为它会导致DNA双链断裂（DSB），这是一种高毒性DNA损伤，通常会导致基因组不稳定和癌症。众所周知，DSB的染色体易位可以促进淋巴瘤的发展。然而，在IR和淋巴瘤抑制诱导的DNA双链断裂修复的调控机制方面仍然存在很大的差距。BIR重复序列泛素结合酶（BIR repeat containing ubiquitin-conjugating enzyme，布鲁斯）是一种具有泛素-蛋白质结合酶（E2）和连接酶（E3）活性的保守蛋白，催化泛素对蛋白质的翻译后修饰。直到最近，布鲁斯才被证明参与细胞凋亡抑制、胞质分裂和小鼠胚胎发生。最近，我们的初步研究提供了第一个迹象表明，布鲁斯是一个抑制淋巴瘤和调节蛋白的DNA修复途径。特别是，我们观察到布鲁斯小鼠对淋巴瘤易感，并且布鲁斯失活的细胞在电离辐射后显示基因组不稳定性和未修复的DSB。我们还观察到，布鲁斯通过调节在DSB位点的早期DNA损伤信号传导蛋白和IR后的下游修复蛋白的积累，在DNA修复级联中的上游步骤起作用。此外，布鲁斯与人类健康具有很强的相关性，因为布鲁斯基因表达水平的降低与人类淋巴瘤相关，并且还与淋巴瘤患者的低存活率相关。基于这些发现，我们推测布鲁斯通过促进DNA DSB修复抑制染色体异常和淋巴瘤发生。我们提出了两个目的来验证这一假设：（1）确定在我们的杂合BRUCEWT/C突变小鼠中发生的淋巴瘤中的染色体易位，以及它们是否由淋巴细胞中程序性和/或一般DSB的受损修复引起。我们还将通过分析人类淋巴瘤组织阵列来确定布鲁斯蛋白水平的降低是否与淋巴瘤的发展相关。(2)确定布鲁斯调节修复蛋白进入DSB位点的机制及其在同源重组（HR）和非同源末端连接（NHEJ，经典和替代）的DSB修复途径中的意义。这项工作是重要的，因为它将是第一个迹象表明，布鲁斯是一个抑制淋巴瘤和调节蛋白在DNA修复。这项工作也是创新的，因为从未预期甚至推测过布鲁斯，一种抗凋亡蛋白，可以调节DNA修复和肿瘤抑制。它通过将布鲁斯置于当前泛素调控途径的上游来挑战当前的泛素范式。这些结果有望为开发能够调节布鲁斯水平和/或活性的新型药物奠定基础，用于创新性干预淋巴瘤和其他由错误DNA修复引起的相关疾病。