Mechanisms of Endogenous DNA Damage Promotion

内源性 DNA 损伤促进机制

• 批准号: 10206079
• 负责人: Kyle M Miller
• 金额: $ 66.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206079
• 关键词: Alzheimer' s Disease; Automobile Driving; Bacterial DNA; Biological Markers; Biological Process; Cancer Diagnostics; Cancer Etiology; Cancer Model; Cells; Closure by clamp; DNA; DNA Binding; DNA Damage; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA Repair Gene; DNA Sequence Alteration; DNA Structure; DNA replication fork; Data; Defect; Diagnosis; Diagnostic; Disease; Disease susceptibility; Drug Targeting; Equilibrium; Escherichia coli; Event; Gene Proteins; Genes; Genome; Genomic Instability; Goals; Heat shock proteins; Human; Human Cloning; Link; Malignant Neoplasms; Maps; Methylation; Mismatch Repair; Modeling; Molecular; Mutagenesis; Mutation; Oncogenes; Oncogenic; Oncoproteins; Output; Oxides; Pathology; Patient-Focused Outcomes; Pharmaceutical Preparations; Phenotype; Proteins; RNA; Reagent; Role; Route; Sampling; Signal Transduction; Single-Stranded DNA; Testing; Therapeutic; Translations; Work; anti-cancer; base; cancer biomarkers; cancer prevention; cost; experimental study; gain of function; genome sequencing; genome-wide; human DNA; human DNA damage; human model; inhibitor/antagonist; innovation; insight; loss of function; loss of function mutation; novel anticancer drug; predictive modeling; protein function; relating to nervous system; screening; success; synthetic construct; transcription factor; transcriptome; translation to humans; tumor; whole genome

Mechanisms of Endogenous DNA Damage Promotion Identification of the oncogenic mechanisms underlying cancer-promoting mutations remains a critical bottleneck in translation of discovered cancer-gene identities into effective anti-cancer strategies. Furthermore, strong correlations of Alzheimer’s disease (AD) with cancers indicate that these mechanisms also underlie AD. Their identification may allow fundamentally new AD pre-disease biomarkers, diagnostic, preventative and possibly therapeutic strategies. The goal of this multi-PI project is to leverage the team’s discovery in Escherichia coli, and its immediate translation to human homologs, of large, diverse, conserved networks of proteins that promote endogenous DNA damage and genome instability when overproduced—the DNA “Damage-up” Proteins (DDPs). DDP identities and mechanisms discovered indicate that many known and unknown overproduced oncoproteins are likely to constitute oncogenic and AD-associated mechanisms in which pathologies arise from destabilization of genomes rather than via the proteins’ other specific cell-biological functions. A network of E. coli DDPs promote endogenous DNA damage and mutation when overproduced, modeling many overproduction oncoproteins. The human homologs are highly enriched among known cancer driving genes, and their RNAs in cancers predict heavy tumor mutation loads and poor patient outcomes. 46% of human homologs sampled promote DNA damage and mutagenesis when overproduced in human cells, demonstrating the power of the E. coli platform for predicting human functions. Unlike genome instability and cancer caused by DNA-repair gene loss-of-function mutations, DDPs promote genome instability as gain-of-function alterations (overproduction), and so potentially can be drugged. DDPs defy previous cancer-gene/protein functional classes because they destabilize genomes but are not DNA-repair genes that suppress mutation rate, but instead are instigators of endogenous DNA damage and genome instability via mechanisms previously poorly defined. This project is aimed at revealing fundamental conserved mechanisms and consequences of endogenous DNA-damage promotion by DDPs using the E. coli model to guide cancer-protein function discovery in human cells. Because the DDPs and their activites are a new and innovative conceptual paradigm, we expect results of this project to re-direct many ongoing efforts in cancer prevention, diagnosis, and treatment. Because vast numbers and kinds of proteins are implicated, and cancer is strongly correlated with AD, increased endogenous DNA damage may be a widespread biomarker for cancer and AD susceptibility.

内源性DNA损伤促进机制 识别致癌机制的潜在致癌突变仍然是一个关键的瓶颈 将发现的癌症基因特性转化为有效的抗癌策略。此外，强 阿尔茨海默病（AD）与癌症的相关性表明这些机制也是AD的基础。他们的 鉴定可以允许从根本上新的AD病前生物标志物，诊断、预防和可能 治疗策略这个多PI项目的目标是利用该团队在大肠杆菌中的发现， 及其直接翻译成人类同系物，大的，多样的，保守的蛋白质网络， 内源性DNA损伤和基因组的不稳定性，当过量生产-DNA“损伤”蛋白（DDP）。 DDP身份和机制的发现表明，许多已知和未知的过度产生的癌蛋白， 很可能构成致癌和AD相关机制，其中病理由不稳定引起 而不是通过蛋白质的其他特定细胞生物学功能。E.大肠杆菌DDPs 促进内源性DNA损伤和突变时，过度生产，建模许多过度生产 癌蛋白人类同源物在已知的癌症驱动基因中高度富集，并且它们的RNA在肿瘤中表达。 癌症预示着肿瘤突变负荷重和患者预后差。46%的人类同源物样本 当在人类细胞中过量产生时，促进DNA损伤和诱变，证明了E. coli平台预测人体功能。与基因组不稳定和DNA修复基因引起的癌症不同， 功能丧失突变，DDP促进基因组不稳定性作为功能获得性改变（过度生产）， 所以可能会被下药DDP无视以前的癌症基因/蛋白质功能类别，因为它们 不稳定的基因组，但不是DNA修复基因，抑制突变率，而是煽动者， 内源性DNA损伤和基因组不稳定性通过以前定义不明确的机制。这个项目是 旨在揭示内源性DNA损伤的基本保守机制和后果 利用E.大肠杆菌模型，以指导人类细胞中的癌症蛋白质功能发现。因为 DDPs及其活动是一个新的和创新的概念范例，我们希望这个项目的结果， 重新指导许多正在进行的癌症预防、诊断和治疗工作。因为大量的物种 的蛋白质是牵连的，癌症与AD密切相关，增加内源性DNA损伤可能 是癌症和AD易感性的广泛生物标志物。