Function of REV3L in limiting oncogenesis via DNA damage tolerance

REV3L 通过 DNA 损伤耐受限制肿瘤发生的功能

基本信息

批准号：
7758283
负责人：
RICHARD D WOOD
金额：
$ 31.96万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-14 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758283
关键词：
Acetylcysteine Affect Aging Amino Acids Bypass Catalytic Domain Cell Death Cell Line Cell Proliferation Cell Survival Cell physiology Cells Characteristics Chromosomal Breaks Chromosomal Instability Chromosomal Stability Chromosomal translocation Chromosome abnormality Chromosomes Complementary DNA DNA DNA Damage DNA Sequence Rearrangement DNA biosynthesis DNA polymerase zeta DNA repair protein DNA-Directed DNA Polymerase Defect Development Embryonic Development Enzymes Event Frequencies Gene Expression Genetic Genetic Recombination Genome Genome Stability Genomic Instability Genomics Growth Health Human Incidence Knockout Mice Knowledge Laboratories Lesion Lymphoma Maintenance Malignant Neoplasms Mammalian Cell Mammary Neoplasms Measurement Measures Mediating Mitosis Monitor Mouse Cell Line Mus Mutation Neoplasm Metastasis Normal Cell Null Lymphocytes Phenotype Physiological Polymerase Proteins Reactive Oxygen Species Reagent Research Role Sister Chromatid Exchange Site Site-Directed Mutagenesis Staging Stress Testing Thymic Lymphoma Tumor Suppressor Genes Tumor-Associated Process cell growth homologous recombination human DNA improved micronucleus mouse model prevent protein expression protein protein interaction public health relevance research study tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): REV3L is the DNA polymerase subunit of pol 6, an enzyme involved in tolerance of genomic damage. REV3L is essential for embryonic development, for reasons that remain to be clarified. We find that Rev3L-defective mammalian cells have high rates of spontaneous chromosome instability, a feature that is also characteristic of many cancers. The PI's laboratory has developed a conditional pol zeta-null mouse, and it appears that a subset of tumors in such mice are preferentially Rev3L-null. Pol 6 may thus be an example of a specialized DNA polymerase that acts as a tumor suppressor gene. The proposed experiments will use a new combination of cellular, genetic, and mouse model approaches to test the extent to which REV3L protects cells against endogenous DNA-damaging stress and chromosomal instability, and to investigate the process of tumor development in the absence of REV3L. The aims are (1) to test the hypothesis that REV3L enables cells to tolerate DNA damage that can disrupt chromosome integrity and interfere with cell proliferation; (2) to determine which domains of the REV3L protein are necessary for normal cell proliferation and genome stability; (3) to test whether loss of REV3L function in mice promotes tumor development. PUBLIC HEALTH RELEVANCE: DNA damaging agents produce mutations that affect human health, aging, and genome instability. Our research suggests that the human DNA repair protein REV3L suppresses tumor formation by helping to prevent genome instability. Knowledge of the REV3L status of tumors could be useful in tailoring therapies, and specific interference with REV3L function could be expected to influence tumor development.

描述（由申请人提供）：Rev3L是POL 6的DNA聚合酶亚基，这是一种涉及基因组损伤的酶。由于尚待澄清的原因，Rev3L对于胚胎开发至关重要。我们发现Rev3L缺陷型哺乳动物细胞具有较高的自发性染色体不稳定性，这一特征也是许多癌症的特征。 PI的实验室已经开发了有条件的pol zeta-null小鼠，并且看来此类小鼠中的肿瘤子集优先是Rev3L无效。因此，POL 6可能是充当肿瘤抑制基因的专用DNA聚合酶的一个例子。提出的实验将使用细胞，遗传和小鼠模型方法的新组合来测试REV3L在多大程度上保护细胞免受内源性DNA损伤应激和染色体不稳定性的程度，并在没有REV3L的情况下研究肿瘤发育的过程。目的是（1）测试Rev3L使细胞耐受DNA损伤的假设，该损伤可能破坏染色体完整性并干扰细胞增殖。（2）确定Rev3L蛋白的哪些结构域对于正常细胞增殖和基因组稳定性是必需的；（3）测试小鼠Rev3L功能的损失是否促进肿瘤的发展。公共卫生相关性：DNA破坏药物会产生影响人类健康，衰老和基因组不稳定性的突变。我们的研究表明，人DNA修复蛋白REV3L通过帮助预防基因组不稳定性来抑制肿瘤的形成。了解肿瘤的REV3L状态的知识可能有助于调整疗法，并且可以预期对Rev3L功能的特定干扰会影响肿瘤的发育。