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APOBEC proteins as drivers of chromosomal translocations in solid cancers

APOBEC 蛋白作为实体癌染色体易位的驱动因素

基本信息

批准号：
10301350
负责人：
Roberto Chiarle
金额：
$ 39.68万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-18 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301350
关键词：
Address Biology Blood Cell Nucleus Cells Chromosomal translocation Chromosome Fragile Sites Cytidine Deaminase DNA DNA Damage DNA Double Strand Break DNA Repair Pathway DNA Sequence Rearrangement DNA Structure DNA biosynthesis Double Strand Break Repair Down-Regulation Enzymes Event Evolution Family Frequencies Generations Genes Genome Genomic Instability Genomics Hematologic Neoplasms Human Immunoglobulin Class Switching Immunoglobulin Gene Rearrangement Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Induced Mutation Inflammation Intrinsic factor Ionizing radiation Lead Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Maps Methods Molecular Mus Mutation Normal Cell Nuclear Oncogenic Pathologic Pattern Physiological Positioning Attribute Probability Proteins Reactive Oxygen Species Recurrence Research Role Signal Transduction Solid Solid Neoplasm Somatic Mutation Specificity Structure Techniques Testing Therapeutic Topoisomerase II Ultraviolet Rays Up-Regulation V(D)J Recombination apolipoprotein B mRNA editing enzyme base cancer cell cancer type cell type density enzyme activity experimental study genome-wide human data in vitro Assay in vivo in vivo Model innovation insight leukemia/lymphoma lymph nodes malignant breast neoplasm malignant stomach neoplasm member mouse model polypeptide repaired replication stress tool treatment response tumor ultraviolet irradiation

项目摘要

Summary Chromosomal translocations are key drivers of oncogenic transformation and frequently determine the biology and response to therapy of cancer cells. The mechanisms that generate the DNA double strand breaks (DSBs) that initiate chromosomal translocations are well known in hematologic cancers but poorly understood in solid tumors. In lymphoma and leukemia, most DSBs that lead to an oncogenic translocation are generated by the activity of enzymes such as RAG1/2 and AID. These enzymes are physiologically responsible for the rearrangements of the immunoglobulin genes, but can initiate a translocation when they aberrantly target other genes. In contrast, in solid tumors where RAG1/2 and AID are largely not expressed, it is unclear what factors initiate DSB formation. Physical factors, such as UV light or irradiation, or factors intrinsic to the DNA structure or replication are thought to be responsible for part of the DSB and translocation formation, but they are insufficient to explain the recurrent patterns of oncogenic translocations in solid tumors. Recently, the APOBEC proteins have been linked to peculiar mutational signatures found in several solid cancers, including lung and breast cancers. Importantly, the APOBEC-dependent mutational signatures typically co-localize with genomic rearrangements such as translocations and somatic copy number alterations (SCNAs). Based on these correlative findings and preliminary experiments, our hypothesis is that APOBEC enzymes could be responsible not only for somatic mutations but also for the formation of chromosomal translocation in solid tumors. We will test this hypothesis by applying innovative sequencing techniques we developed in our lab to identify and map recurrent translocations induced by APOBEC proteins in different cell types. We will apply these techniques both in in vitro assays as well as to in vivo models of translocation formation. The demonstration that APOBEC protein can initiate translocation formation has the potential to provide a key mechanistic link that is currently missing to explain recurrent structural aberrations in cancer. From this demonstration, a variety of new research lines will open including potential therapeutic applications aimed at blocking APOBEC activity to reduce genomic instability in cancer.

概括染色体易位是致癌转化的关键驱动因素，并且经常决定生物学和对癌细胞治疗的反应。产生 DNA 双链断裂的机制引发染色体易位的 DSB（DSB）在血液癌症中众所周知，但人们对其知之甚少在实体瘤中。在淋巴瘤和白血病中，大多数导致致癌易位的 DSB 都是产生的通过 RAG1/2 和 AID 等酶的活性。这些酶在生理上负责免疫球蛋白基因的重排，但当它们异常地靶向其他基因时可以启动易位基因。相比之下，在 RAG1/2 和 AID 基本上不表达的实体瘤中，尚不清楚是什么因素启动 DSB 形成。物理因素，例如紫外线或辐射，或 DNA 结构固有的因素或复制被认为负责部分 DSB 和易位形成，但它们是不足以解释实体瘤中致癌易位的复发模式。近日，APOBEC 蛋白质与多种实体癌中发现的特殊突变特征有关，包括肺癌和癌症。乳腺癌。重要的是，APOBEC 依赖性突变特征通常与基因组共定位重排，例如易位和体细胞拷贝数改变（SCNA）。基于这些相关发现和初步实验，我们的假设是 APOBEC 酶可能是不仅负责体细胞突变，而且还负责固体中染色体易位的形成肿瘤。我们将通过应用我们在实验室开发的创新测序技术来检验这一假设识别并绘制不同细胞类型中由 APOBEC 蛋白诱导的反复易位。我们将申请这些技术既可用于体外测定，也可用于易位形成的体内模型。这 APOBEC 蛋白可以启动易位形成的证明有可能提供关键目前尚缺乏解释癌症中反复出现的结构畸变的机制联系。从这里示范，将开放各种新的研究线，包括针对以下疾病的潜在治疗应用：阻断 APOBEC 活性以减少癌症中的基因组不稳定性。