How does TREX2 maintain and alter chromosomes?

TREX2如何维持和改变染色体？

基本信息

批准号：
8925829
负责人：
EDWARD PAUL HASTY
金额：
$ 35.27万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925829
关键词：
3-methyladenine-DNA glycosylase Abbreviations Address Affect Animals Antineoplastic Agents Antithymoglobulin Biological Process Bloom Syndrome Bypass Camptothecin Cancer Etiology Catalytic Domain Cells Chromosomal Breaks Chromosomal Rearrangement Chromosome Structures Chromosomes Co-Immunoprecipitations Collaborations Colorectal Cancer DNA DNA Binding Domain DNA Double Strand Break Data Defect Development Double Strand Break Repair Drug Targeting Embryo Etiology Exhibits Exonuclease Fanconi&apos s Anemia Genetic Genetic Recombination Genome Genomic Instability Grant Health Sciences Investigation Knowledge Lesion Light Loss of Heterozygosity Maintenance Malignant Neoplasms Mediating Medicine Methyl Methanesulfonate Microsatellite Instability Mismatch Repair Mitomycins Mus Mutate Nature New York Organ Outcome Paper Pathway interactions Phosphodiesterase I Physiological Physiology Play Proliferating Cell Nuclear Antigen Proteins Publishing Reporter Role Topoisomerase Tumor Suppressor Proteins Ubiquitin Ubiquitination Viola adenine phosphoribosyltransferase college embryonic stem cell genome integrity homologous recombination human TREX2 protein hydroxyurea in vivo insight mutant novel public health relevance repaired stem telomere tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Genome instability is a hallmark of cancer. Yet genome maintenance and mechanisms of genome instability are not clearly understood. This proposal continues the collaboration between Dr. Paul Hasty at the Health Science Center at San Antonio and Dr. Cristina Montagna at Albert Einstein College of Medicine in New York. They will explore the involvement of TREX2 in both the suppression and development of genomic instability. TREX2 is a 3'?5' exonuclease that removes 3' mismatches in DNA. However, its biological function is not known. We found that TREX2-deletion increased the level of isochromatid breaks and gross chromosomal rearrangements (GCRs) demonstrating that TREX2 maintains intact chromosome structure; however, we also found that TREX2 fused mismatch inverted repeats to induce palindromic chromosomes that were unstable and susceptible to continual rearrangements that involve multiple chromosomes. In addition, we found that TREX2 enables genomic instability in cancer prone cells. Thus, TREX2 both maintains and alters genome integrity. Yet just how TREX2 accomplishes these antithetical outcomes is not known. Since TREX2 deletion caused breaks and rearrangements, we thought it participated in DNA double strand break (DSB) repair. However, TREX2-deleted cells have elevated DSB repair capacity. Therefore, we hypothesized that TREX2 suppressed the formation of DSBs by maintaining replication forks (RFs). To support this hypothesis, we found TREX2 associated with proteins in the error-free postreplication repair (EF-PRR) pathway and enabled PCNA (proliferating cell nuclear antigen) ubiquitination; a key EF-PRR function that suppresses RF stalling through two mechanisms: translesion synthesis and template switch. We wish to further these investigations. In Aim 1 we will address our hypothesis that TREX2 suppresses DSB formation and GCRs though EF-PRRmediated lesion bypass and in Aim 2 we will address our hypothesis that TREX2 enables genomic instability through EF-PRR and its genetic integration with other tumor suppressor pathways. Finally in Aim 3 we propose to alter TREX2 in mice to observe its biological function in the whole animal. These studies will elucidate the dual role that TREX2 plays in preserving and altering genomic integrity and will provide mechanistic insight to both the suppression and creation of genomic instability that causes cancer. Such knowledge will be useful to evaluate TREX2 as an anti-cancer drug target.

描述（由申请人提供）：基因组不稳定性是癌症的一个标志。然而，基因组维护和基因组不稳定的机制尚不清楚。该提案延续了圣安东尼奥健康科学中心的 Paul Hasty 博士和纽约阿尔伯特·爱因斯坦医学院的 Cristina Montagna 博士之间的合作。他们将探索 TREX2 在基因组不稳定性的抑制和发展中的作用。 TREX2 是一种 3'→5' 核酸外切酶，可消除 DNA 中的 3' 错配。然而，其生物学功能尚不清楚。我们发现TREX2缺失增加了等染色单体断裂和总染色体重排（GCR）的水平，这表明TREX2保持了完整的染色体结构；然而，我们还发现 TREX2 融合错配反向重复序列以诱导不稳定且易受涉及多条染色体的持续重排的回文染色体的影响。此外，我们发现 TREX2 使易患癌症的细胞的基因组不稳定。因此，TREX2 既维持又改变基因组完整性。然而 TREX2 如何实现这些相反的结果尚不清楚。由于TREX2缺失导致断裂和重排，我们认为它参与了DNA双链断裂（DSB）修复。然而，TREX2 缺失的细胞具有增强的 DSB 修复能力。因此，我们假设 TREX2 通过维持复制叉 (RF) 来抑制 DSB 的形成。为了支持这一假设，我们发现 TREX2 与无错复制后修复 (EF-PRR) 途径中的蛋白质相关，并启用 PCNA（增殖细胞核抗原）泛素化； EF-PRR 的一个关键功能，可通过两种机制抑制 RF 失速：跨损伤合成和模板切换。我们希望进一步开展这些调查。在目标 1 中，我们将提出我们的假设，即 TREX2 通过 EF-PRR 介导的病变旁路抑制 DSB 形成和 GCR；在目标 2 中，我们将提出我们的假设，即 TREX2 通过 EF-PRR 及其与其他肿瘤抑制途径的遗传整合来实现基因组不稳定。最后，在目标 3 中，我们建议改变小鼠中的 TREX2，以观察其在整个动物中的生物学功能。这些研究将阐明 TREX2 在保存和改变基因组完整性方面发挥的双重作用，并将为抑制和产生导致癌症的基因组不稳定性提供机制见解。这些知识将有助于评估 TREX2 作为抗癌药物靶点。