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Mechanisms of Endogenous DNA Damage Promotion

内源性 DNA 损伤促进机制

基本信息

批准号：
10658879
负责人：
Kyle M Miller
金额：
$ 64.89万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658879
关键词：
Alzheimer&apos 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 Genes Genome Genomic Instability Goals Heat shock proteins Homologous Gene Human Human Cloning Link Malignant Neoplasms Maps Methylation Mismatch Repair Modeling Molecular Mutagenesis Mutation Oncogenes Oncogenic Oncoproteins Output Pathology Patient-Focused Outcomes Pharmaceutical Preparations Phenotype Production Proteins RNA Reagent Role Route Sampling Signal Transduction Single-Stranded DNA Testing Therapeutic Translations Work anti-cancer cancer biomarkers cancer prevention cost experimental study gain of function genome sequencing genome-wide human DNA human DNA damage human model inhibitor innovation insight loss of function loss of function mutation neural novel anticancer drug predictive modeling protein function screening success synthetic construct transcription factor transcriptome translation to humans tumor whole genome

项目摘要

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损伤的促进机制识别致癌突变的致癌机制仍然是一个关键的瓶颈。将已发现的癌症基因特性转化为有效的抗癌策略。此外，强势阿尔茨海默病(AD)与癌症的相关性表明，这些机制也是AD的基础。他们的鉴定可能从根本上允许新的AD疾病前生物标志物、诊断性、预防性和可能的治疗策略。这个多PI项目的目标是利用该团队在大肠杆菌中的发现，以及它直接翻译成人类同源物，这是一种大型的、多样化的、保守的蛋白质网络，促进当过度生产时，内源性DNA损伤和基因组不稳定--DNA“损伤”蛋白(DDP)。已发现的DDP特性和机制表明许多已知和未知的癌蛋白过度生产可能构成致癌和AD相关的机制，在这些机制中，病理产生于不稳定而不是通过蛋白质的其他特定细胞生物学功能。大肠埃希菌DDP网络当生产过剩时，会促进内源性DNA损伤和突变，从而模拟许多生产过剩癌蛋白。在已知的致癌基因中，人类同源基因高度丰富，它们的RNA在癌症预示着巨大的肿瘤突变负荷和糟糕的患者预后。46%的人类同源物被采样当在人类细胞中过度生产时，会促进DNA损伤和突变，证明了E。用于预测人体功能的Coli平台。不同于基因组不稳定和DNA修复基因引起的癌症功能丧失突变，DDP促进基因组不稳定为功能获得改变(生产过剩)，因此可能会被下药。DDPS挑战了以前的癌症基因/蛋白质功能类，因为它们破坏基因组稳定，但不是抑制突变率的DNA修复基因，而是内源性DNA损伤和基因组不稳定通过以前不清楚的机制。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使用大肠杆菌模型的DDP促进，以指导人类细胞中癌症-蛋白质功能的发现。因为 DDP及其活动是一种新的创新概念范式，我们期待这个项目的结果重新引导许多正在进行的癌症预防、诊断和治疗工作。因为数量众多，种类繁多与蛋白质有关，癌症与AD密切相关，内源性DNA损伤增加可能成为癌症和AD易感性的广泛生物标志物。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evolutionary action of mutations reveals antimicrobial resistance genes in Escherichia coli.

DOI：
10.1038/s41467-022-30889-1
发表时间：
2022-06-09
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

Interdependent progression of bidirectional sister replisomes in E. coli.

DOI：
10.7554/elife.82241
发表时间：
2023-01-09
期刊：
ELIFE
影响因子：
7.7
作者：
Chen, Po Jui;McMullin, Anna B.;Visser, Bryan J.;Mei, Qian;Rosenberg, Susan M.;Bates, David
通讯作者：
Bates, David

Two mechanisms of chromosome fragility at replication-termination sites in bacteria.

DOI：
10.1126/sciadv.abe2846
发表时间：
2021-06
期刊：
Science advances
影响因子：
13.6
作者：
Mei Q;Fitzgerald DM;Liu J;Xia J;Pribis JP;Zhai Y;Nehring RB;Paiano J;Li H;Nussenzweig A;Hastings PJ;Rosenberg SM
通讯作者：
Rosenberg SM

Stress-Induced Mutagenesis, Gambler Cells, and Stealth Targeting Antibiotic-Induced Evolution.

DOI：
10.1128/mbio.01074-22
发表时间：
2022-06-28
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer.

DOI：
10.1038/s41588-023-01504-w
发表时间：
2023-10
期刊：
NATURE GENETICS
影响因子：
30.8
作者：
McCann, Jennifer L.;Cristini, Agnese;Law, Emily K.;Lee, Seo Yun;Tellier, Michael;Carpenter, Michael A.;Beghe, Chiara;Kim, Jae Jin;Sanchez, Anthony;Jarvis, Matthew C.;Stefanovska, Bojana;Temiz, Nuri A.;Bergstrom, Erik N.;Salamango, Daniel J.;Brown, Margaret R.;Murphy, Shona;Alexandrov, Ludmil B.;Miller, Kyle M.;Gromak, Natalia;Harris, Reuben S.
通讯作者：
Harris, Reuben S.