DNA Repair

DNA修复

基本信息

批准号：
8175300
负责人：
ANDRE A. NUSSENZWEIG
金额：
$ 124.01万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8175300
关键词：
Achievement Affect Animals Antigen Receptors Area Ataxia B-Cell Lymphomas Burkitt Lymphoma Cell Proliferation Cells Chimeric Proteins Chromatin Structure Chromosomal Instability Chromosomal translocation Chromosomes Complex DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Rearrangement DNA biosynthesis DNA lesion Defect Detection Development Double Strand Break Repair Future Gene Amplification Genetic Recombination Genome Stability Genomic Instability Germ Cells Goals Hematopoietic Neoplasms Human Immunologic Deficiency Syndromes Inborn Genetic Diseases Karyotype Knock-out Knockout Mice Lead Lymphocyte Lymphoid Maintenance Malignant Neoplasms Mammalian Cell Meiotic Recombination Monitor Mus Nijmegen Breakage Syndrome Nonhomologous DNA End Joining Oncogenes Oncogenic Pathway interactions Physiological Predisposition Premature aging syndrome Proteins Radiation Tolerance Reaction Reciprocal Translocation Research Signal Transduction Solid Neoplasm System TP53 Gene Inactivation Telangiectasis Transgenic Mice base cell type mouse model repaired response

项目摘要

The major focus of this project is to understand how cells monitor and repair DNA damage. Defects in either the surveillance or repair of damaged DNA can lead to chromosomal instability and cancer. For example, inherited disorders affecting cellular responses to DNA damage, such as Nijmegen breakage syndrome and ataxia telangiectasia are characterized by increased susceptibility to lymphoid cancer, extreme radiation sensitivity and immunodeficiency. We are generating knockout and transgenic mouse models that have specific defects in DNA double strand break (DSB) repair. Recently, we characterized mice that were defective in non-homologous end joining, the major pathway for repairing DSBs in mammalian cells. We found that these mice displayed premature aging, a defect in cellular proliferation, a complete block in lymphocyte development and extreme radiation sensitivity. Surprisingly, however, the mice were not prone to cancer. However, a further inactivation of the p53 tumor suppressor gene markedly increased cancer susceptibility, such that these "double knockout" mice invariably succumbed to B-cell lymphomas that resembled human Burkitt's lymphoma. Other mouse models for DNA double strand break repair are being generating including animals that lack the Nijmegen breakage sydrome protein.

该项目的主要重点是了解细胞如何监测和修复 DNA 损伤。受损 DNA 的监测或修复缺陷可能导致染色体不稳定和癌症。例如，影响细胞对 DNA 损伤反应的遗传性疾病，如奈梅亨断裂综合征和共济失调性毛细血管扩张症，其特征是对淋巴癌的易感性增加、极度辐射敏感性和免疫缺陷。我们正在构建在 DNA 双链断裂 (DSB) 修复方面具有特定缺陷的基因敲除和转基因小鼠模型。最近，我们对非同源末端连接缺陷的小鼠进行了表征，非同源末端连接是哺乳动物细胞中修复 DSB 的主要途径。我们发现这些小鼠表现出过早衰老、细胞增殖缺陷、淋巴细胞发育完全受阻以及极端的辐射敏感性。然而令人惊讶的是，这些小鼠并不容易患癌症。然而，p53肿瘤抑制基因的进一步失活显着增加了癌症易感性，使得这些“双敲除”小鼠总是死于类似于人类伯基特淋巴瘤的B细胞淋巴瘤。其他用于 DNA 双链断裂修复的小鼠模型正在建立中，包括缺乏奈梅亨断裂综合症蛋白的动物。