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The role of transcription factor proteins in mutagenesis at regulatory sites

转录因子蛋白在调控位点诱变中的作用

基本信息

批准号：
10552569
负责人：
Raluca Gordan
金额：
$ 33.68万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552569
关键词：
Affinity Base Pair Mismatch Binding Binding Sites Biological Assay Cell physiology Cells Complex Computer Analysis Computer Models Computing Methodologies DNA DNA Binding DNA Repair DNA Repair Enzymes DNA Sequence Alteration DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase Data Development Foundations Future Gene Expression Genetic Recombination Genome Genomics Human In Vitro Lesion Location Malignant Neoplasms Measures Methods Mismatch Repair Modeling Molecular Mutagenesis Mutation Pathologic Mutagenesis Pattern Process Proteins Recurrence Replication Error Role Signal Transduction Site Somatic Mutation Specificity Statistical Methods Techniques Testing The Cancer Genome Atlas Training Untranslated RNA Validation Work Yeasts base cancer cell cancer genome cancer type cost design driver mutation falls genomic predictors high throughput screening in vivo innovation next generation prevent repair enzyme repaired transcription factor validation studies whole genome yeast genetics

项目摘要

ABSTRACT More than 90% of cancer somatic mutations fall in non-coding regions of the genome. While the vast majority of these mutations are expected to be passengers, a small fraction could act as drivers by disrupting regulatory interactions between transcription factors (TFs) and DNA, leading to dysregulation of gene expression. Despite the increased availability of whole-genome cancer somatic mutation data, identifying non-coding driver mutations in TF binding sites remains a challenge, likely because of gaps in our understanding of the mutagenic processes acting on regulatory DNA. There is increasing evidence that TFs bound to the genome can interfere with normal DNA replication and repair, which could lead to increased mutation rates. However, the precise molecular mechanisms of these interactions are poorly understood. The current project will address this gap in our understanding of mutagenesis in TF binding sites by using new experimental techniques and computational models to directly investigate the molecular mechanisms by which TF binding can lead to genetic mutations. Our overarching hypothesis is that TFs bound to genomic sites containing DNA lesions can lead to inefficient repair/correction of the lesions, and consequently to increased mutation rates. Among DNA lesions we will focus on base mismatches, which are important precursors for a majority of cancer mutations, and are frequently generated in the genome during DNA replication, recombination, and even repair of other lesions. Thus, mismatches retained in cancer genomes due to being bound by TF proteins are expected to have a large contribution to the hyper-mutation signal observed at TF binding sites. It is therefore critical to characterize the TF-DNA binding landscape in the presence of DNA mismatches (Aim 1), and to thoroughly investigate the mechanisms by which TF binding to mismatches can lead to genetic mutations (Aim 2). Overall, our proposed work represents a first step toward determining whether the enrichment of cancer mutations in TF binding sites is due, at least in part, to DNA-bound TFs that act as roadblocks for DNA mismatch correction and repair. Longer term, a thorough understanding of the role of TFs in mutagenesis at regulatory DNA will be instrumental for developing accurate methods to identify regulatory driver mutations in cancer.

摘要超过90%的癌症体细胞突变位于基因组的非编码区。虽然绝大多数在这些突变中，有一小部分可能是乘客，一小部分可能是司机，转录因子（TF）和DNA之间的相互作用，导致基因表达失调。尽管全基因组癌症体细胞突变数据的可用性增加， TF结合位点的突变仍然是一个挑战，可能是因为我们对TF结合位点的理解存在差距。作用于调节DNA的诱变过程。越来越多的证据表明，转录因子与基因组结合，可以干扰正常的DNA复制和修复，这可能会导致突变率增加。然而，在这方面，这些相互作用的精确分子机制知之甚少。本项目将解决这是我们通过使用新的实验技术对TF结合位点突变的理解中的差距，计算模型，直接调查TF结合可能导致的分子机制，基因突变我们的总体假设是，与含有DNA损伤的基因组位点结合的TF可以导致损伤的修复/校正效率低下，并因此导致突变率增加。在DNA中我们将重点关注碱基错配，这是大多数癌症突变的重要前兆，并且在DNA复制、重组甚至修复其他细胞的过程中经常在基因组中产生。病变因此，由于被TF蛋白结合而保留在癌症基因组中的错配预期会对在TF结合位点观察到的超突变信号有很大的贡献。因此，在存在DNA错配的情况下表征TF-DNA结合景观（目标1），并彻底研究TF与错配结合可能导致基因突变的机制（目标2）。总的来说，我们提出的工作代表了确定癌症突变的富集是否与癌症的发生有关的第一步。 TF结合位点至少部分是由于DNA结合的TF作为DNA错配校正的障碍和修复。从长远来看，彻底了解转录因子在调控DNA突变中的作用将是有助于开发准确的方法来识别癌症中的调节驱动突变。