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Arsenic carcinogenesis and disruption of histone variant H3.3 assembly

砷致癌和组蛋白变体 H3.3 组装的破坏

基本信息

批准号：
10631227
负责人：
Max Costa
金额：
$ 52.99万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-06 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10631227
关键词：
Amino Acids Arsenic Attenuated Binding Binding Proteins Carcinogens Cell Cycle Arrest Cell Cycle Progression Cells ChIP-seq Chromatin Modeling Chromatin Structure Chromosome Segregation Coupled DNA Repair Defect Development Ectopic Expression Enhancers Environment Epigenetic Process Exposure to Gene Expression Genes Genetic Transcription Genome Stability Genomic Instability Heterochromatin Histone H3 Histone H3.3 Histones Link Lung Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of urinary bladder Maps Mass Spectrum Analysis Mediating Messenger RNA Metals Molecular Chaperones Mus Nucleosomes Nude Mice Persons Play Poly A Poly(A) Tail Polyadenylation Post-Translational Protein Processing Process Property Proteins RNA Regulator Genes Regulatory Element Renal carcinoma Role Site Skin Cancer Structure Testing Therapeutic Intervention Tissues Variant arsenic carcinogenesis arsenic-induced carcinogenesis cancer type carcinogenesis carcinogenicity cell growth cell transformation exposed human population genome-wide histone modification human disease in vivo innovation knock-down mutant novel overexpression prevent promoter stem therapeutically effective transcriptome transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY Arsenic has been identified as a prominent causal agent in skin, lung, bladder, and liver cancers. Arsenic contamination impacts hundreds of millions of people in the world. The carcinogenicity of arsenic coupled with an alarmingly large number of people exposed creates an urgency for studying and understanding its carcinogenic mechanisms so effective therapeutic intervention can be initiated. Unlike most other genes, canonical histone messenger RNAs (mRNAs) such as histone H3.1 mRNA do not end with a poly(A) tail, instead they have a stem-loop structure at their 3’ end. Stem-loop binding protein (SLBP) attaches to the stem- loop RNA structure that is required for 3’-processing of the canonical histone mRNA. Previously we found that arsenic exposure downregulates SLBP levels, allowing the canonical histone H3.1 mRNA to acquire a poly(A) tail. Polyadenylation of H3.1 mRNA appeared to be carcinogenic, since it induced transcriptional deregulation, cell cycle arrest, and genomic instability, and facilitated anchorage-independent cell growth and tumor formation in nude mice. These effects were likely resulting from disruption of variant histone H3.3 assembly, because genome-wide histone mapping showed that polyadenylation of H3.1 mRNA compromised the H3.3 assembly at the sites critical for transcription, cell identity, and heterochromatin spreading. H3.3 plays important roles in transcription, efficient DNA damage repair, proper segregation of chromosomes, and development. The knockdown of H3.3, which mimics disruption of H3.3 assembly, induced cell transformation. Furthermore, H3.3 mutants have been linked to various type of cancers, underscoring importance of H3.3 in carcinogenesis. Based on these observations, we hypothesize that disruption of H3.3 assembly resulting from polyadenylation of canonical histone H3.1 mRNA is a significant contributor to arsenic-induced carcinogenesis. To test this hypothesis, we will determine the mechanisms by which polyadenylated canonical histone H3.1 mRNA disrupts assembly of the variant H3.3 in Aim 1, determine whether defective H3.3 assembly is responsible for arsenic-induced aberrant transcription, cell cycle arrest as well as genomic instability in Aim 2, and determine the role for disruption of H3.3 assembly in arsenic-induced cell transformation and explore whether arsenic exposure disrupts H3.3 assembly in vivo in Aim 3. The significance and innovation of these studies lie in the potential to reveal disruption of H3.3 assembly as a novel mechanism of arsenic-induced carcinogenesis.

项目总结砷已被确定为皮肤癌、肺癌、膀胱癌和肝癌的主要致病因素。砷污染影响着世界上数亿人。砷的致癌性与令人震惊的是，大量的人暴露在病毒中，迫切需要研究和理解其致癌机制，因此可以启动有效的治疗干预。与大多数其他基因不同，组蛋白信使RNA(MRNAs)如组蛋白H3.1mRNA不以聚(A)尾结束，相反，它们的3‘端有一个茎环结构。茎环结合蛋白(SLBP)附着在茎上- 组蛋白3‘-加工所需的环状RNA结构。之前我们发现，砷暴露下调SLBP水平，使典型的组蛋白H3.1 mRNA获得PolyA 尾巴。H3.1基因的多聚腺苷酸化似乎是致癌的，因为它会导致转录失控，细胞周期停滞和基因组不稳定，并促进锚定非依赖性细胞生长和肿瘤在裸鼠体内形成。这些影响可能是由于组蛋白H3.3变异体组装的破坏所致，因为全基因组组蛋白图谱显示H3.1 mRNA的多腺苷基化损害了H3.3 在转录、细胞特性和异染色质扩散的关键部位组装。H3.3实演在转录、有效的DNA损伤修复、适当的染色体分离以及发展。H3.3基因的敲除模拟了H3.3组装的破坏，诱导了细胞转化。此外，H3.3突变与各种类型的癌症有关，强调了H3.3在癌症中的重要性致癌。基于这些观察，我们假设H3.3组装的中断导致组蛋白H3.1多聚腺苷酸化是砷中毒的重要诱因致癌。为了验证这一假说，我们将确定多聚腺苷酸化的机制规范性组蛋白H3.1 mRNA破坏Aim 1中变异体H3.3的组装，确定是否存在缺陷 H3.3组装与砷诱导的异常转录、细胞周期停滞以及基因组有关 AIM 2的不稳定性，并确定H3.3组装在砷诱导的细胞中的破坏作用探讨砷暴露是否扰乱H3.3在AIM 3体内的组装这些研究的创新之处在于有可能揭示H3.3组装的破坏是一种新的机制砷诱导的致癌作用。