Mechanisms of BER in Genomic Integrity and Epigenetic Regulation
BER 在基因组完整性和表观遗传调控中的机制
基本信息
- 批准号:10726878
- 负责人:
- 金额:$ 4.48万
- 依托单位:
- 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:2020-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Aberrant DNA MethylationAgingAnimalsArchaeaBacteriaBase Excision RepairsBindingCytosineDNADNA MethylationDNA Repair EnzymesDNA glycosylaseDeaminationDiseaseEnsureEnzymesEpigenetic ProcessExcisionFaceGene ExpressionGenetic DiseasesGenomicsGoalsGuanineHealthHumanIn VitroLearningMalignant NeoplasmsMammalsMediatingMethylationModelingModificationMutationNaturePathway interactionsPlantsPoint MutationPolymerasePost-Translational Protein ProcessingProcessResearchSiteSpecificitySumoylation PathwaySystemTestingThymineUracilVertebratesbasedemethylationenzyme activityepigenetic regulationgenome integrityhuman DNAhuman diseaseinterestnovel therapeutic interventionoxidationrecruitrepair enzymerepaired
项目摘要
An overarching goal of our research is to understand how the base excision repair (BER) pathway maintains
genomic integrity and mediates epigenetic regulation, and how deficiencies in BER impact human health. A
major focus is to discover how DNA glycosylases, which initiate BER, find and excise damaged or modified
forms of 5-methylcytosine (mC). The most abundant modified DNA base in nature, mC is critical for epigenetic
regulation in plants and animals and for restriction modification in archaea and bacteria. However, cytosine
methylation also poses a danger because mC deaminates to T, generating G/T mispairs and C to T mutations
that threaten genomic and epigenetic integrity and causes human diseases including cancer. Countering this
threat are three different types of glycosylases that excise T from G/T mispairs; TDG and MBD4 in mammals
and MIG in archaea and bacteria. While most glycosylases excise bases that are foreign to DNA (e.g., uracil)
these enzymes face the daunting task of removing thymine bases arising by mC deamination but not those in
the vast background of A:T pairs or in polymerase-generated G/T mispairs. Because glycosylase action on
undamaged DNA is mutagenic, the specificity of these G/T glycosylases is critical, yet it is poorly defined. The
current paradigm holds that specificity involves recognition of the mismatched guanine. We will rigorously test
this model and investigate other potential specificity factors, to define the mechanism of G/T glycosylase
specificity. Our studies will reveal features of TDG and MBD4 that may account for inefficient repair of mC
deamination, a potential cause of point mutations implicated in cancer and genetic disease. BER also functions
in epigenetic regulation by serving to “erase” mC through active DNA demethylation. An established pathway
in vertebrates involves oxidation of mC by a TET enzyme to give three oxy-mC products (hmC, fC, caC),
excision of fC or caC by TDG, and subsequent BER to yield unmodified C. Our studies will address major gaps
in the understanding of this essential pathway, by defining how TDG recognizes and removes fC and caC and
how it is recruited to sites of DNA demethylation. We are also interested in how post-translational modifications
regulate BER, and our current focus is on determining how TDG is regulated by SUMO modification. TDG is
sumoylated at a single site, and it has a SUMO-interacting motif (SIM) that binds SUMO domains, including an
intramolecular SUMO. While TDG is considered a model for understanding how sumoylation can regulate
enzyme activity, many fundamental questions remain. Our studies will reveal how sumoylation alters TDG
activity and how the SIM mediates these effects. We will also define mechanisms of SUMO conjugation and
deconjugation and learn how the SIM modulates these processes. An in vitro conjugation-deconjugation
system will be used to test the paradigm that sumoylation of TDG is required to regulate its product release
and ensure faithful completion of TDG-initiated BER. Results of these studies will inform how BER deficiencies
impact human health and could suggest new therapeutic approaches for treating diseases including cancer.
我们研究的首要目标是了解碱基切除修复(BER)途径是如何维持的
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alex C Drohat其他文献
Alex C Drohat的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alex C Drohat', 18)}}的其他基金
Mechanisms of BER in Genomic Integrity and Epigenetic Regulation
BER 在基因组完整性和表观遗传调控中的机制
- 批准号:
10390444 - 财政年份:2020
- 资助金额:
$ 4.48万 - 项目类别:
Mechanisms of BER in Genomic Integrity and Epigenetic Regulation
BER 在基因组完整性和表观遗传调控中的机制
- 批准号:
10605583 - 财政年份:2020
- 资助金额:
$ 4.48万 - 项目类别:
Mechanisms of BER in Genomic Integrity and Epigenetic Regulation
BER 在基因组完整性和表观遗传调控中的机制
- 批准号:
10606489 - 财政年份:2020
- 资助金额:
$ 4.48万 - 项目类别:
Structure and mechanism of CpG specific DNA glycosylases
CpG特异性DNA糖基化酶的结构和机制
- 批准号:
7931177 - 财政年份:2009
- 资助金额:
$ 4.48万 - 项目类别:
Structure and mechanism of CpG specific DNA glycosylases
CpG特异性DNA糖基化酶的结构和机制
- 批准号:
7175459 - 财政年份:2005
- 资助金额:
$ 4.48万 - 项目类别:
Structure and mechanism of CpG specific DNA glycosylases
CpG特异性DNA糖基化酶的结构和机制
- 批准号:
7146414 - 财政年份:2005
- 资助金额:
$ 4.48万 - 项目类别:
Structure and Mechanism of CpG specific DNA glycosylases
CpG 特异性 DNA 糖基化酶的结构和机制
- 批准号:
8535460 - 财政年份:2005
- 资助金额:
$ 4.48万 - 项目类别:
Structure and Mechanism of CpG specific DNA glycosylases
CpG 特异性 DNA 糖基化酶的结构和机制
- 批准号:
8536824 - 财政年份:2005
- 资助金额:
$ 4.48万 - 项目类别:
相似海外基金
Pexophagy regulation in live animals and its role in aging and longevity
活体动物的 Pexophagy 调节及其在衰老和长寿中的作用
- 批准号:
10566172 - 财政年份:2022
- 资助金额:
$ 4.48万 - 项目类别:
Myocardial Infarct in Aging Animals and dATP Therapy
老龄动物心肌梗死和 dATP 治疗
- 批准号:
9565690 - 财政年份:2017
- 资助金额:
$ 4.48万 - 项目类别:
Analysis of the bone metabolism failure in the aging animals and establishment of the preventive maintenance plan based on the animal welfare
老龄动物骨代谢衰竭分析及基于动物福利的预防性维护计划制定
- 批准号:
16K15057 - 财政年份:2016
- 资助金额:
$ 4.48万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Deciphering early events of infection in yopung and aging animals using caenorhabditis elegans as a model host
使用秀丽隐杆线虫作为模型宿主破译yopung和衰老动物的早期感染事件
- 批准号:
374271-2009 - 财政年份:2011
- 资助金额:
$ 4.48万 - 项目类别:
Postgraduate Scholarships - Doctoral
Deciphering early events of infection in yopung and aging animals using caenorhabditis elegans as a model host
使用秀丽隐杆线虫作为模型宿主破译yopung和衰老动物的早期感染事件
- 批准号:
374271-2009 - 财政年份:2010
- 资助金额:
$ 4.48万 - 项目类别:
Postgraduate Scholarships - Doctoral
Deciphering early events of infection in yopung and aging animals using caenorhabditis elegans as a model host
使用秀丽隐杆线虫作为模型宿主破译yopung和衰老动物的早期感染事件
- 批准号:
374271-2009 - 财政年份:2009
- 资助金额:
$ 4.48万 - 项目类别:
Postgraduate Scholarships - Doctoral
Comparative evolutionary studies on the expmssion of dementia-related genes in aging nonhuman animals
老年非人类动物痴呆相关基因表达的比较进化研究
- 批准号:
14360188 - 财政年份:2002
- 资助金额:
$ 4.48万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Roles of oxidatively modified proteins in the brain of aging animals : Intervention by moderate regular exercise
氧化修饰蛋白质在衰老动物大脑中的作用:适度定期运动的干预
- 批准号:
12672126 - 财政年份:2000
- 资助金额:
$ 4.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
THE STUDY OF RISK ASSESSMENT FOR ENVIRONMENTAL POLLUTANTS USING IMMUNOLOGICAL PARAMETERS IN AGING ANIMALS WITH LUNG DISEASES.
使用患有肺病的老龄动物的免疫参数进行环境污染物风险评估的研究。
- 批准号:
10680524 - 财政年份:1998
- 资助金额:
$ 4.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Nonlinear analysis of the hemodynamics in the artificial heart animals as the aging acceleration model
作为老化加速模型的人工心脏动物血流动力学的非线性分析
- 批准号:
06558118 - 财政年份:1994
- 资助金额:
$ 4.48万 - 项目类别:
Grant-in-Aid for Scientific Research (B)