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Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations

DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制

基本信息

批准号：
10543990
负责人：
Polina V Shcherbakova
金额：
$ 34.19万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-06 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543990
关键词：
Affect Alleles Amino Acids Animal Model Automobile Driving Biochemical Biological Biological Assay Biological Models Bypass Cell Proliferation Cell division Cells Classification Colon Colorectal Cancer DNA Polymerase II DNA Structure DNA-Directed DNA Polymerase Data Defect Development Endometrial Carcinoma Environment Epithelial Cells Etiology Exonuclease Future Genes Genomic Instability Goals Human Laboratories Link Malignant Neoplasms Modeling Mus Mutagenesis Mutation Nature Nucleotides Pathogenicity Phenotype Phosphodiesterase I Polymerase Polymers Predisposition Prognosis Property Proteins Reaction Recurrence Research Role Specificity Testing Variant Work Yeast Model System Yeasts cancer risk correctional system cost design gain of function improved innovation insight loss of function mutant mutation carrier novel personalized medicine polymerization prevent reconstitution therapy outcome tool treatment response tumor tumorigenesis variant detection

项目摘要

Mutations in the POLE gene encoding DNA polymerase e (Pole) have been linked to the development of colorectal and endometrial cancers with extremely high levels of hypermutation. The mechanism through which Pole variants cause hypermutability remains puzzling. Because amino acid residues in the exonuclease domain are preferentially affected, POLE mutations were originally thought to act by inactivating exonucleolytic proofreading. However, subsequent research by our laboratory challenged this concept. Mutator effects of cancer-associated variants in model systems greatly exceed the effect of proofreading deficiency (in the case of the most recurrent variant, P286R - by two orders of magnitude). PoleP286R mice were also found to be much more cancer-prone than proofreading-deficient Pole mice. Thus, factors other than loss of exonuclease must be responsible for the elevated mutagenesis and cancer risk. The goal of this application is to decipher the mechanisms that drive genomic instability in POLE-mutant tumors. Preliminary studies led us to propose that, for many Pole exonuclease domain variants, the main consequence is not merely the loss of exonuclease but a dramatically increased DNA polymerase activity, which affects the overall contribution of Pole to replication and interferes with the function of other mutation avoidance mechanisms. This is a highly innovative hypothesis, since it defines POLE variants in tumors as gain-of-function variants rather than loss-of-function as was previously thought. We will test this hypothesis by pursuing two Specific Aims. In Aim 1, we will use purified four-subunit Pole to characterize the biochemical effects of cancer-associated mutations. In Aim 2, we will define the mechanisms of the mutator effects of Pole variants in proliferating cells. These studies will help understand the etiology of a significant proportion of colorectal and endometrial cancers and may pinpoint new targets for the development of personalized therapies for POLE mutation carriers. The biochemical and cell- based assays we will establish in the course of this work will also be instrumental for assessing the functional significance of multiple poorly understood POLE variants detected in tumors.

编码DNA聚合酶e （POLE）的POLE基因突变与糖尿病的发生有关