Studies of Lymphoma Suppression and DNA Repair

淋巴瘤抑制和 DNA 修复的研究

• 批准号: 9226101
• 负责人: CHUNYING DU
• 金额: $ 4.25万
• 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/9226101
• 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）：地球上某些矿物产生的电离辐射（IR）代表了对人的主要环境健康危害，因为它会导致DNA双链断裂（DSB）（DSB），高毒性的DNA病变通常会导致基因组不稳定性和癌症。众所周知，DSB的染色体易位可以促进淋巴瘤的发育。然而，在IR和淋巴瘤抑制诱导的修复DNA DSB的调节机制方面仍然存在显着差距。含有泛素偶联酶（Bruce）的BIR重复是一种保守的蛋白质，具有嵌合泛素 - 蛋白 - 蛋白结合酶（E2）和连接酶（E3）活性，可通过泛素催化蛋白质的翻译后修饰。直到最近，Bruce仅显示出参与凋亡抑制，细胞因子和小鼠胚胎发生。最近，我们的初步研究提供了第一个迹象，即Bruce是DNA修复途径中淋巴瘤和调节蛋白的抑制剂。特别是，我们观察到，布鲁斯小鼠易受淋巴瘤的影响，并且在电离辐射电离后，带有布鲁斯的细胞灭活了基因组不稳定性和未经修复的DSB。我们还观察到，布鲁斯通过调节DSB部位的积累，对IR后的早期DNA损伤信号蛋白和下游修复蛋白的积累，在DNA修复级联的上游起作用。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有关，并且与淋巴瘤患者的存活率较低有关。基于这些发现，我们假设布鲁斯通过促进DNA DSB修复来抑制染色体异常和淋巴作用。我们提出了两个旨在检验这一假设的目的：（1）确定在杂合Brucewt/c突变小鼠中开发的淋巴瘤中的染色体易位，以及它们是否是由淋巴细胞中程序化和/或一般DSB的损害修复而导致的。我们还将通过分析人类淋巴瘤组织阵列来确定降低的Bruce蛋白水平是否与淋巴瘤的发育有关。 （2）确定Bruce调节修复蛋白进入DSB部位的机制及其在同源重组（HR）（HR）（HR）和非同源结局（NHEJ）（NHEJ，Classic and Classic and nhej）中的含义。这项提出的工作很重要，因为这将是Bruce是淋巴瘤和DNA修复中调节蛋白的抑制剂的第一个迹象。这项工作也具有创新性，因为它从未被预期甚至猜测，抗凋亡蛋白的布鲁斯可以调节DNA修复和抑制肿瘤。它通过将布鲁斯上游放置当前泛素调节途径的上游来挑战当前的泛素范式。预计这些结果将为开发能够调节布鲁斯对淋巴瘤创新干预的水平和/或活性的新型药物的基础奠定基础，这是由于DNA修复故障导致的其他相关疾病。