Chromosome fragility and translocations in lymphocytes

淋巴细胞中的染色体脆性和易位

基本信息

批准号：
8863191
负责人：
Davide Filippo Robbiani
金额：
$ 21.19万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8863191
关键词：
Activated B-Lymphocyte Acute T Cell Leukemia Affinity Antibodies B-Cell Activation B-Cell Acute Lymphoblastic Leukemia B-Cell Development B-Lymphocytes BCL2 gene BCL9 gene Biochemical Biological Bone Marrow Breast Burkitt Lymphoma CCND1 gene Cancer Etiology Cell Culture Techniques Cells Chromatin Chromosomal Instability Chromosomal translocation Chromosome Deletion Chromosome Fragility Chromosomes Code Collection Complex DNA DNA Binding DNA Damage DNA Double Strand Break DNA Sequence DNA Sequence Rearrangement DNA Structure DNA biosynthesis Follicular Lymphoma Gene Rearrangement Generations Genes Genetic Recombination Genome Genomic Instability Genomics Goals Histones Human Human Characteristics IGH@ gene cluster IgK Immune response Immunoglobulin Class Switching Immunoglobulin Genes Immunoglobulin Switch Recombination Label Lead Lymphocyte Lymphoma MYC gene Malignant Neoplasms Methods Molecular Mus Mutate Oncogenes Oncogenic Peptide Signal Sequences Physiological Predisposing Factor Proliferating Prostate Reaction Recruitment Activity Recurrence Research Role Site Source Structure of germinal center of lymph node T-Lymphocyte Techniques Testing Time Transgenic Organisms Ursidae Family V(D)J Recombination activation-induced cytidine deaminase c-myc Genes cofactor deep sequencing genome integrity genome-wide leukemia/lymphoma lung Carcinoma novel overexpression pathogen programs public health relevance recombinase research study tumor

项目摘要

DESCRIPTION (provided by applicant): Chromosome fragility and translocations in lymphocytes Summary DNA double-strand breaks pose a particularly serious threat to genome integrity, as they predispose to chromosome rearrangements, which can lead to cancer. Recurrent chromosome translocations and deletions are found across a multitude of malignancies (such as lymphomas, leukemias, and carcinomas of the lung, breast and prostate) and involve hundreds of cancer genes (1, 2). However, little is known about the molecular mechanisms governing these aberrant DNA recombinations, and particularly about the cause of fragility of specific genes. Under physiologic conditions, programmed DNA breaks are obligate intermediates during the assembly and diversification reactions of antibody genes. The RAG1/2 recombinase breaks DNA in developing lymphocytes during the assembly of the variable gene segments (V(D)J recombination). In activated B cells, Activation-Induced cytidine Deaminase (AID) causes DNA breaks while altering antibody effector functions during class switch recombination (CSR). Tumors of lymphocytes (lymphomas) often bear hallmark oncogenic translocations involving antibody genes, and the physiologically occurring DNA breaks at these loci are thought to be a predisposing factor (3, 4). However, the source of DNA damage at the oncogene partners involved in these translocations is less clear. B lymphocytes are rapidly dividing cells that proliferate in distinct bursts: first during B cell development in the bone marrow at a time when RAG1/2 is expressed, and later in germinal centers when AID is expressed. RAG1/2, AID and DNA replication are all associated with DNA damage (5, 6). AID causes DNA breaks at the c-myc oncogene and lymphoma-associated chromosome translocations (7, 8). Moreover, AID causes collateral DNA damage at hundreds of other genes in activated B cells, and genome- wide DNA breaks by AID can lead to chromosome deletions and translocations, including some that are found in human B cell lymphoma (9, 10). In contrast, despite a large body of circumstantial evidence, the parameters by which RAG1/2 is mistargeted to generate lymphomagenic aberrations remain not well understood. In two specific aims we propose to test the hypothesis that RAG1/2 damages the B cell genome by mechanisms that are not limited to its action at RSS sites. First, we will examine the DNA damage by RAG1/2 to the genome of primary developing B cells. Second, we will define the landscape of RAG1/2 induced chromosome rearrangements. The long-term goal of the proposed research is to obtain a comprehensive molecular understanding of the genesis of chromosome translocations in B lymphocytes.

描述（由适用提供）：淋巴细胞中的染色体脆性和易位摘要DNA双链断裂对基因组完整性构成了特别严重的威胁，因为它们易于染色体重排，这可能导致癌症。在多种恶性肿瘤（例如肺，乳腺癌和前列腺癌）中发现了复发性染色体易位和缺失，并涉及数百种癌症基因（1，2）。然而，关于管理这些异常DNA重组的分子机制，尤其是特定基因脆弱性的原因，知之甚少。在生理条件下，编程的DNA断裂是抗体基因的组装和多样化反应期间的强制性中间体。 RAG1/2重组酶在可变基因片段组装过程中会破坏发育中的淋巴细胞中的DNA（V（d）J重组）。活化的B细胞，激活诱导的胞苷脱氨酶（AID）会导致DNA断裂，同时在类开关重组（CSR）期间改变抗体效应子功能。淋巴细胞（淋巴瘤）的肿瘤通常具有涉及抗体基因的癌性易位，并且在这些局部存在物理发生的DNA断裂被认为是诱发因素（3，4）。但是，这些易位涉及的癌基因伴侣的DNA损伤来源不太清楚。 B淋巴细胞正在迅速分裂，以不同的爆发形式增殖：首先在表达RAG1/2时在骨髓中的B细胞发育过程中，然后在表达辅助时在生发中心。 RAG1/2，AID和DNA复制都与DNA损伤有关（5，6）。辅助会导致C-Myc癌基因和淋巴瘤相关的染色体易位的DNA断裂（7，8）。此外，AID会在活化的B细胞中引起数百个其他基因的附带DNA损伤，并且通过辅助基因组全基因组DNA破裂会导致染色体缺失和翻译，包括在人B细胞淋巴瘤中发现的一些（9，10）。相比之下，尽管有大量的间接证据，但对RAG1/2进行错误定位以产生淋巴细差畸变的参数尚不清楚。在两个具体的目标中，我们提出了以下假设，即RAG1/2通过不限于其在RSS位点作用的机制损害B细胞基因组。首先，我们将检查RAG1/2对原发性B细胞的基因组的DNA损伤。其次，我们将定义RAG1/2诱导染色体重排的景观。拟议研究的长期目标是获得对B淋巴细胞中染色体易位的发生的全面分子理解。