Studies of Lymphoma Suppression and DNA Repair

淋巴瘤抑制和 DNA 修复的研究

• 批准号: 8297090
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297090
• 关键词: Affect; Apoptosis; Ataxia-Telangiectasia-Mutated protein kinase; 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 Pathway; DNA lesion; DNA repair protein; Data; Development; Disease; Double Strand Break Repair; Embryonic Development; Environmental Health; Enzyme Gene; Etiology; Event; Gene Expression; Genetic; Genetic Recombination; Genome Stability; 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; base; chromatin modification; gamma-Glutamyl Hydrolase; genetic regulatory protein; homologous recombination; improved; innovation; killings; man; mutant; novel; programs; repaired; sensor; 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the discovery of novel regulatory mechanisms for lymphoma suppression and for ionizing radiation-induced DNA damage repair are ultimately expected to improve our understanding of the pathology and etiology of lymphoma and of other malignancies in general. Therefore, the proposed work is relevant to the part of NIH's mission for opening new avenues for developing therapeutic strategies aimed at eliminating lesions that lead to the initiation, maintenance, and progression of cancer.

描述（由申请人提供）：由地球上某些矿物质产生的电离辐射（IR）对人类构成重大环境健康危害，因为它会导致DNA双链断裂（DSB），这是一种剧毒DNA损伤，通常会导致基因组受损不稳定和癌症。众所周知，DSB 处的染色体易位可以促进淋巴瘤的发展。然而，对于 IR 和淋巴瘤抑制诱导的修复 DNA DSB 的调节机制的了解仍然存在重大差距。含有泛素结合酶 (BRUCE) 的 BIR 重复序列是一种保守蛋白，具有嵌合泛素蛋白结合酶 (E2) 和连接酶 (E3) 活性，可催化泛素对蛋白质的翻译后修饰。直到最近，BRUCE 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，我们的初步研究首次表明 BRUCE 是淋巴瘤的抑制因子和 DNA 修复途径中的调节蛋白。特别是，我们观察到 BRUCE 小鼠易患淋巴瘤，并且 BRUCE 失活的细胞在电离辐射后表现出基因组不稳定性和未修复的 DSB。我们还观察到，BRUCE 通过调节 DSB 位点的早期 DNA 损伤信号蛋白和 IR 之后的下游修复蛋白的积累，在 DNA 修复级联的上游发挥作用。此外，BRUCE与人类健康密切相关，因为BRUCE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，我们假设 BRUCE 通过促进 DNA DSB 修复来抑制染色体异常和淋巴瘤发生。我们提出了两个目的来检验这一假设：（1）确定我们的杂合 BRUCEWT/C 突变小鼠中发生的淋巴瘤中的染色体易位，以及它们是否是由淋巴细胞中程序性和/或一般 DSB 修复受损引起的。我们还将通过分析人类淋巴瘤组织阵列来确定 BRUCE 蛋白水平的降低是否与淋巴瘤的发展相关。 (2) 确定BRUCE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修复途径中的含义。这项拟议的工作意义重大，因为它将首次表明 BRUCE 是淋巴瘤的抑制因子和 DNA 修复中的调节蛋白。这项工作的创新性还在于，此前从未预期甚至推测过BRUCE这种抗凋亡蛋白能够调节DNA修复和肿瘤抑制。它将 BRUCE 置于当前泛素监管途径的上游，挑战了当前的泛素范式。这些结果预计将为开发能够调节 BRUCE 水平和/或活性的新型药物奠定基础，以创新干预由错误 DNA 修复引起的淋巴瘤其他相关疾病。 公共健康相关性：拟议的研究与公共健康相关，因为发现淋巴瘤抑制和电离辐射诱导的 DNA 损伤修复的新调节机制最终有望提高我们对淋巴瘤和其他恶性肿瘤的病理学和病因学的理解。一般的。因此，拟议的工作与 NIH 的使命相关，即为开发旨在消除导致癌症发生、维持和进展的病变的治疗策略开辟新途径。