Microsatellite variability within transcribed regions of genes involved in cancer

癌症相关基因转录区域内的微卫星变异

• 批准号: 7364766
• 负责人: MARGARET J KOVACH
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF TENNESSEE CHATTANOOGA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364766
• 关键词: Address; Aging-Related Process; Binding; Biological; Biological Assay; Biological Markers; Cancer cell line; Candidate Disease Gene; Cell Line; Cells; Classification; Code; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Comparative Study; CpG Islands; Cytosine; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Structure; Data; Daughter; Defect; Disease Progression; Elements; Epigenetic Process; Frameshift Mutation; Functional RNA; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Hereditary Nonpolyposis Colorectal Neoplasms; High-Frequency Microsatellite Instability; Human; Human Genome; Hypermethylation; In Vitro; Laboratories; Length; Light; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Methylation; Microsatellite Instability; Microsatellite Repeats; Mismatch Repair; Mission; Modeling; Modification; Molecular; Mutation; Northern Blotting; Numbers; Pathway interactions; Play; Positioning Attribute; Process; Promoter Regions; Proteins; Public Health; RNA Splicing; Rate; Regulatory Element; Replication Error; Research; Role; Sampling; Short Tandem Repeat; Site; Structure; System; Tandem Repeat Sequences; Transcript; Transcriptional Regulation; Tumor Suppressor Proteins; Variant; bisulfite; cancer type; carcinogenesis; chromatin remodeling; gene repression; genome sequencing; mRNA Stability; normal aging; repair enzyme; repaired; transcription factor; tumor progression

DESCRIPTION (provided by applicant): Genomic instability is a molecular feature common to the progression of many cancers, particularly those that demonstrate genetic defects in mismatch repair (MMR) enzymes. The primary role of the MMR system is to maintain genomic stability by removing replication errors from DNA. This repair pathway was originally implicated in human cancer through an association between microsatellite instability (MSI) in colorectal tumors in hereditary nonpolyposis colon cancer (HNPCC). Microsatellites are ubiquitous short tandem-repeat sequences widely and randomly distributed throughout the human genome. They are acutely prone to replication errors that result in expansions and contractions of the repeat unit due to misalignment of the template and daughter strands. A number of human genes associated with cancer contain microsatellite repeats within the coding and non-coding regions of the transcribed sequences. It has been suggested that instability of repeat sequences in the coding regions of several of these genes, plays a role in the progression of disease, presumably by gene inactivation through the introduction of frameshift mutations. Variability of microsatellite repeat lengths in non-coding regions of transcripts has also been implicated in the regulation of gene expression. We hypothesize that the genes in the molecular pathway(s) of cancer progression are subject to gene regulation by microsatellite repeat sequence variability, and that the accumulation of these variants through defects in MMR or the normal aging process contribute to cancer progression by influencing gene expression and chromatin remodeling as it relates to the positioning of regulatory elements, mRNA stability and methylation status of CpG islands. The completion of the human genome sequence offers the opportunity to screen for and evaluate the role of these simple sequence repeats in genome maintenance and gene expression. Ultimately, we will advance a specific mission of the NCI: to gain a more complete understanding of genetic and epigenetic determinants of cancer and the biological mechanisms underlying cancer initiation and progression. To achieve these goals our research aims are to (1) evaluate and correlate repeat variability with cancer-associated changes in colorectal cell lines, (2) examine and correlate methylation status of CpG islands with repeat variability and replication error (RER) classification and (3) assay gene expression and activity levels in genes demonstrating microsatellite variability. The results of these studies should contribute to our current understanding of cancer, identify molecular markers of cancer progression and will shed light on atypical modulators of gene expression. / RELEVANCE TO PUBLIC HEALTH: The overall goal of this study is to investigate the hypothesis that the genes in the molecular pathway(s) of cancer progression are subject to transcriptional regulation by microsatellite repeat sequence variability. Ultimately, we will advance a specific mission of the NCI: to gain a more complete understanding of genetic and epigenetic determinants of cancer and the biological mechanisms underlying cancer initiation and progression.

描述（由申请人提供）：基因组不稳定性是许多癌症进展的共同分子特征，特别是那些表现出错配修复（MMR）酶遗传缺陷的癌症。MMR系统的主要作用是通过从DNA中去除复制错误来维持基因组稳定性。这种修复途径最初通过遗传性非息肉病性结肠癌（HNPCC）中结直肠肿瘤中的微卫星不稳定性（MSI）之间的关联而与人类癌症有关。微卫星是广泛随机分布在人类基因组中的一种普遍存在的短串联重复序列。它们非常容易发生复制错误，由于模板和子链的未对准而导致重复单元的扩展和收缩。许多与癌症相关的人类基因在转录序列的编码区和非编码区内含有微卫星重复序列。已经表明，这些基因中的几个的编码区中的重复序列的不稳定性在疾病的进展中起作用，推测是通过引入移码突变而使基因失活。转录本非编码区微卫星重复序列长度的变异性也与基因表达调控有关。我们假设癌症进展的分子途径中的基因受到微卫星重复序列变异性的基因调控，并且这些变异通过MMR缺陷或正常衰老过程的积累通过影响基因表达和染色质重塑而促进癌症进展，因为它涉及调控元件的定位、mRNA稳定性和CpG岛的甲基化状态。人类基因组序列的完成为筛选和评估这些简单重复序列在基因组维持和基因表达中的作用提供了机会。最终，我们将推进NCI的一项具体使命：更全面地了解癌症的遗传和表观遗传决定因素以及癌症发生和发展的生物学机制。为了实现这些目标，我们的研究目标是（1）评估重复变异性并将其与结直肠细胞系中的癌症相关变化相关联，（2）检查CpG岛的甲基化状态并将其与重复变异性和复制错误（RER）分类相关联，以及（3）检测显示微卫星变异性的基因中的基因表达和活性水平。这些研究的结果应该有助于我们目前对癌症的理解，确定癌症进展的分子标志物，并将揭示基因表达的非典型调节剂。与公共卫生的关系：本研究的总体目标是研究癌症进展分子途径中的基因受微卫星重复序列变异性的转录调控的假设。最终，我们将推进NCI的一项具体使命：更全面地了解癌症的遗传和表观遗传决定因素以及癌症发生和发展的生物学机制。