How does TREX2 maintain and alter chromosomes?

TREX2如何维持和改变染色体？

• 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
• 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' 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

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）：基因组不稳定是癌症的一个标志。然而，基因组的维持和基因组不稳定的机制尚不清楚。这项提议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在抑制和发展基因组不稳定性中的作用。TREX2是3'？去除DNA中3‘不匹配的5’外切酶。然而，其生物学功能尚不清楚。我们发现TREX2缺失增加了同染色单体断裂和总染色体重排（GCRs）的水平，表明TREX2保持了完整的染色体结构；然而，我们也发现TREX2融合错配反向重复序列诱导回文染色体，这些回文染色体不稳定，容易受到涉及多个染色体的连续重排的影响。此外，我们发现TREX2使易癌变细胞的基因组不稳定。因此，TREX2既维持又改变基因组的完整性。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缺失的细胞具有更高的DSB修复能力。因此，我们假设TREX2通过维持复制分叉（RFs）来抑制dsb的形成。为了支持这一假设，我们发现TREX2与无错误复制后修复（EF-PRR）途径中的蛋白质相关，并使PCNA（增殖细胞核抗原）泛素化；一个关键的EF-PRR功能，通过两个机制抑制RF延迟：平移合成和模板切换。我们希望进一步进行这些调查。在目标1中，我们将阐述TREX2通过EF-PRR介导的病变旁路抑制DSB形成和gcr的假设；在目标2中，我们将阐述TREX2通过EF-PRR及其与其他肿瘤抑制途径的遗传整合使基因组不稳定的假设。最后，在Aim 3中，我们提出在小鼠中改变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在保持和改变基因组完整性方面的双重作用，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。