c-myc DNA breaks and c-myc-IgH locus translocations: roles of AID and oxidation

c-myc DNA 断裂和 c-myc-IgH 基因座易位：AID 和氧化的作用

基本信息

批准号：
7865093
负责人：
Janet M. Stavnezer
金额：
$ 20.56万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7865093
关键词：
Acetylcysteine Address Affect Amino Acids Antibodies B-Cell Lymphomas B-Lymphocytes Bacterial Toxins Cells Chromosomal translocation Cytidine Deaminase DNA DNA Double Strand Break DNA lesion DNA repair protein Deaminase Deamination Event Frequencies Generations Genes Genetic Recombination Glutathione IGH@ gene cluster IgE Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Genes Immunoglobulin M Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulins Lead Lesion Ligation MYC gene Malignant Neoplasms Mediating Mitochondria Multiple Myeloma Mus Mutation Oncogenes Process Proteins Publishing Reaction Reactive Oxygen Species Recruitment Activity Respiration Role Signal Transduction Site activation-induced cytidine deaminase c-myc Genes cell transformation improved oxidation pathogen public health relevance repaired response variable region gene

项目摘要

DESCRIPTION (provided by applicant): Antibody (immunoglobulin, Ig) class switch causes B lymphocytes to switch from producing IgM to producing IgG, IgA or IgE, which improves the ability of the antibody to remove pathogens and bacterial toxins from the body. Class switching occurs by an intrachromosomal DNA recombination event that must be carefully controlled in order to avoid aberrant recombination with other chromosomes (translocations). However, occasional translocations do occur. Sometimes they result in B lymphomas or myelomas due to translocations of the Ig genes to a chromosomal site encoding an oncogene, e.g. c-myc, which induces aberrant expression of the c-myc gene. This application proposes to investigate how DNA double-strand breaks (DSBs) are introduced into the mouse c-myc gene and the role of activation-induced cytidine deaminase (AID) in the process of c-myc-IgH translocations. In Aim 1, we will investigate the hypothesis that reactive oxygen species (ROS) induce DNA lesions that lead to DSBs in the c-myc gene, and also stimulate the deamination activity of AID, as deamination occurs by an oxidation reaction. In Aim 2, we will investigate whether AID has additional activities besides its deaminase activity that contribute to creating c- myc-IgH translocations. In Aim 3, we will investigate the role of the 10 amino acids at the C terminus of AID, which is required for class switch recombination but not for somatic hypermutation, and has been shown to repress c-myc-IgH translocations. We will examine the hypothesis that DNA repair proteins involved in switch recombination are recruited by the C terminus. PUBLIC HEALTH RELEVANCE: This project investigates the events that initiate the generation of B cell lymphomas and myelomas. We will study how DNA breaks are introduced into the c-myc oncogene when normal mouse B cells are induced to undergo the normal process of antibody class switching in response to activation signals. These DNA breaks can result in translocations of the c-myc oncogene to the immunoglobulin (Ig) heavy (H) chain gene locus, which increases expression of the c-myc gene, and this can lead to cell transformation and malignancy. We will study whether the protein that is required for initiating DNA break formation in the IgH genes during antibody class switching (activation-induced cytidine deaminase, AID) is required for introducing DNA breaks into the c-myc gene, and whether AID has additional roles that lead to the translocations between the IgH genes and c-myc genes. We will also investigate the function of AID itself during normal class switching, as this affects translocations between the c-myc gene and the IgH locus.

描述（由申请人提供）：抗体（免疫球蛋白，IG）类开关导致B淋巴细胞从产生IgM转变为产生IgG，IgA或IgE，从而提高了抗体去除体内的病原体和细菌毒素的能力。类别切换是通过肉体内DNA重组事件进行的，必须仔细控制，以避免与其他染色体（易位）异常重组。但是，偶尔会发生易位。有时，由于Ig基因转移到编码癌基因的染色体位点，它们会导致B淋巴瘤或骨髓瘤，例如c-myc，诱导c-myc基因的异常表达。该应用建议研究如何将DNA双链断裂（DSB）引入小鼠C-MYC基因，以及激活诱导的胞苷脱氨酶（AID）在C-Myc-EGR易位过程中的作用。在AIM 1中，我们将研究一个假说，即活性氧（ROS）诱导导致C-MYC基因中DSB的DNA病变，并刺激AID的脱氨酸活性，因为氧化反应发生脱氨酸。在AIM 2中，我们将调查AID除了其脱氨酶活动外是否有其他活动，这些活动有助于创建C- MYC-EGH易位。在AIM 3中，我们将研究10个氨基酸在C末端的AID末端的作用，这是类开关重组所必需的，但不能用于体细胞超松碎，并且已被证明会抑制C-Myc-igh的易位。我们将研究以下假设：C末端募集了与开关重组有关的DNA修复蛋白。公共卫生相关性：该项目调查了引发B细胞淋巴瘤和脊髓瘤的事件。当诱导正常小鼠B细胞以响应激活信号响应正常的小鼠B细胞时，我们将研究如何将DNA断裂引入c-myc癌基因。这些DNA断裂会导致C-Myc癌基因转移到免疫球蛋白（Ig）重（H）链基因基因座，从而增加C-MYC基因的表达，这可能导致细胞转化和恶性肿瘤。我们将研究在将DNA断裂引入C-MYC基因的抗体类转换期间IGH基因中启动DNA断裂形成所需的蛋白质，以及辅助剂是否具有导致IGH GENES和C-MYC基因之间易作的其他作用。我们还将在正常类切换过程中研究辅助自身的功能，因为这会影响C-MYC基因和IGH基因座之间的易位。