Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
批准号:
10293848
负责人:
Suse Broyde
金额:
$36.79万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-06-01 至 2026-04-30
关键词:
AcetylationAddressAffectAirAirborne Particulate MatterAntineoplastic AgentsAromatic CompoundsAromatic Polycyclic HydrocarbonsBase SequenceBindingBiological MarkersBypassCharacteristicsChemical StructureChemicalsComplementCryoelectron MicroscopyCytosineDNADNA DamageDNA SequenceDNA lesionDNA-Directed DNA PolymeraseDNA-protein crosslinkDiseaseEnvironmental ExposureEnvironmental PollutantsExcisionFailureFoodFossil FuelsFree EnergyGenomicsGuanineHistone AcetylationHomologous GeneHumanHuman GenomeImpairmentInduced MutationLeadLesionMalignant NeoplasmsMethodsModelingModificationMolecularMolecular ConformationMutagenesisMutationNatureNucleosomesNucleotide Excision RepairOrthologous GeneOutcomePathologic MutagenesisPeptidesPharmaceutical PreparationsPharmacotherapyPlayPolymerasePositioning AttributePredispositionProcessPropertyProteinsReactive Oxygen SpeciesResistanceRibonucleotidesRiskRotationShapesSiteSourceStructureTestingThermodynamicsTobaccoUltraviolet RaysWaterWorkXeroderma PigmentosumYeastsadductbasecarcinogenicitychemotherapycrosslinkdesigndisease-causing mutationexhaustexperimental studyfrontiergene repairgenotoxicityhelicasehuman diseaseinsightinterestmolecular dynamicsmutantpredictive toolsrepairedsoundstereochemistrysuperfund sitetranscription factor TFIIHtumorwasting
中文摘要
项目总结
人类基因组不断受到攻击,来源包括环境污染物,其他
外源性来源,包括药物治疗、内源性活性氧物种和紫外线。在这些人中
病变/加合物是来自多环芳香化合物的病变/加合物,多环芳香化合物是化石燃料的广泛副产品
在有毒废物堆放场、超级垃圾场、我们的空气、食物和水中发现燃烧。由此造成的DNA损伤
导致突变导致癌症。然而,并不是所有的dna损伤都具有同样的致癌性,因为它们具有突变性。
倾向各不相同:一系列的过程决定了它们是被修复的,还是为了诱变而存活下来的
DNA聚合酶的无差错旁路。人类核苷酸切除修复(NER)是一种重要的
切除了许多这样的DNA损伤。NER的极端重要性在毁灭性的人类身上得到了证明
色素性干皮病,由NER基因突变引起。值得注意的是,一些损伤迅速
修复,有些很慢,有些是耐药的,因此特别是遗传毒性,这一现象很糟糕
明白了。同样,我们对dna损伤旁路机制的理解也存在差距。
可导致突变或无错误结果的聚合酶。该项目的目标是提供
对DNA损伤致突变性的令人困惑的变异性的机械洞察,重点放在损伤的关键步骤上
识别修复和突变旁路,以产生完整的新分子和动态理解
使用分子动力学模拟,以前所未有的原子细节显示病变的诱变倾向。
我们的总体假设是病变的结构和它的碱基序列上下文决定了它
总的致突变倾向。在目标1中,我们将利用一组精选的DNA损伤/加合物,其结构
在大小和形状上有很大的差异,放置在不同的序列上下文中,以确定结构、能量和
含有病变的DNA与RAD4/XPC结合时的动态特征
人XPC损伤识别蛋白。我们将揭示那些为获得生产性认可而捆绑在一起的人是如何导致
切除不同于那些未能做到这一点的人。在目标2中,我们将确定TFIIH中的人XPD解旋酶是如何,
通过拖延、处理不同大小和形状的病变来验证NER病变的存在,以及
导致人类疾病的XPD突变如何抑制XPD的功能。在目标3中,我们将确定
不同核小体位置的病变结构对核小体施加不同的扭曲及其方式
选定的组蛋白乙酰化调节这些扭曲,以促进或抑制修复通路。在Aim 4中,我们
研究内源和外源DNA多肽的交联性损伤,以确定如何选择DNA
旁路聚合酶在不同的DNA序列环境中对它们进行无差错或突变处理。
专注于最具突变性的损伤,我们的工作将有助于识别适当的生物标记物
为了确定患癌症的风险,提前设计修复较少的化疗药物,以及
产生一个预测工具,以识别由人类肿瘤不同病变诱导的突变热点序列。
英文摘要
PROJECT SUMMARY
The human genome is constantly attacked from sources that include environmental pollutants, other
exogenous origins that include drug treatment, endogenous reactive oxygen species, and UV light. Among the
lesions/adducts are ones derived from polycyclic aromatic compounds, widespread byproducts of fossil fuel
combustion found at toxic waste dumps, superfund sites, in our air, food and water. The resulting DNA lesions
cause mutations that lead to cancer. However, not all DNA lesions are equally carcinogenic, as their mutagenic
propensities vary: a cascade of processes determines whether they are repaired, or survive for mutagenic or
error-free bypass by DNA polymerases. Human nucleotide excision repair (NER) is a key mechanism for
removal of many such DNA lesions. The vital importance of NER is demonstrated in the devastating human
disorder xeroderma pigmentosum, caused by mutations in NER genes. Notably, some lesions are rapidly
repaired, some slowly, and some are resistant and thus particularly genotoxic, a phenomenon that is poorly
understood. Likewise, there is a gap in our understanding of the mechanisms underlying DNA lesion bypass by
polymerases that can lead to a mutagenic or error-free outcome. The objective of this project is to provide
mechanistic insights into the puzzling variability of DNA lesion mutagenicity, focusing on the key steps of lesion
recognition for repair and mutagenic bypass, to yield integrated new molecular and dynamic understanding of
lesion mutagenic proclivity in unprecedented atomistic detail, using molecular dynamics simulations.
Our overall hypothesis is that the structure of the lesion and its base sequence context determine its
overall mutagenic propensity. In Aim 1, we will utilize a selected set of DNA lesions/adducts whose structures
differ greatly in size and shape, placed in differing sequence contexts, to determine structural, energetic and
dynamic characteristics of the lesion-containing DNAs as they bind to Rad4/XPC, the yeast homolog of the
human XPC lesion recognition protein. We will reveal how those that bind for productive recognition leading to
excision differ from those that fail to do so. In Aim 2 we will determine how the human XPD helicase in TFIIH,
that verifies the presence of lesions for NER by stalling, processes lesions of different sizes and shapes, and
how XPD mutations that cause human disease inhibit XPD’s function. In Aim 3 we will determine how differing
lesion structures in varying nucleosomal positions impose different distortions on the nucleosome and how
selected histone acetylations modulate these distortions, to promote or inhibit access for repair. In Aim 4 we
investigate endogenous and exogenous DNA peptide crosslink lesions, to determine how selected DNA
bypass polymerases process them error-free or mutagenically, in differing DNA sequence contexts.
Focusing on the most mutagenic lesions, our work will facilitate identification of appropriate biomarkers
for determining risk of developing cancer, advance design of chemotherapy drugs that are less repaired, and
yield a predictive tool to identify mutational hotspot sequences induced by different lesions in human tumors.
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会议论文
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
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批准号:10460604
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项目类别:
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资助金额:$37.2万
-
财政年份:2016
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负责人:Suse Broyde
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依托单位:
Environmental Carcinogen-DNA Adducts: NER Recognition
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批准号:9275988
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项目类别:
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资助金额:$35.66万
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财政年份:2016
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负责人:Suse Broyde
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依托单位:
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
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批准号:10612958
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项目类别:
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资助金额:$35.61万
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财政年份:2016
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负责人:Suse Broyde
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依托单位:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
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批准号:7956119
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项目类别:
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资助金额:$0.08万
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财政年份:2009
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负责人:Suse Broyde
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依托单位:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
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批准号:7723185
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项目类别:
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资助金额:$0.05万
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财政年份:2008
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负责人:Suse Broyde
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依托单位:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
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批准号:7601434
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项目类别:
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资助金额:$0.03万
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财政年份:2007
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负责人:Suse Broyde
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依托单位:
Aromatic Amine DNA Structures--Mutagenic Relevance
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批准号:6522395
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项目类别:
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资助金额:$23.54万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
DNA Lesion Structures: Mutagenicity and Repair
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批准号:7280349
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项目类别:
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资助金额:$28.15万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
Aromatic Amine DNA Structures--Mutagenic Relevance
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批准号:6915508
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项目类别:
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资助金额:$28.13万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
DNA Lesion Structures: Mutagenicity and Repair
-
批准号:7876627
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项目类别:
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资助金额:$28.42万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
DNA Lesion Structures: Mutagenicity and Repair
-
批准号:7634396
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项目类别:
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资助金额:$28.44万
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财政年份:1997
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依托单位:
Aromatic Amine DNA Structures--Mutagenic Relevance
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批准号:6369568
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项目类别:
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资助金额:$24.2万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
DNA Lesion Structures: Mutagenicity and Repair
-
批准号:7140909
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项目类别:
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资助金额:$28.93万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
DNA Lesion Structures: Mutagenicity and Repair
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批准号:7474530
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项目类别:
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资助金额:$28.21万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
AF AND AAF MODIFIED DNA STRUCTURES--MUTAGENIC RELEVANCE
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批准号:2769970
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项目类别:
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资助金额:$13.25万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
Aromatic Amine-DNA Lesions: Mutagenicity and Repair
-
批准号:8460862
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项目类别:
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资助金额:$27.04万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
Aromatic Amine-DNA Lesions: Mutagenicity and Repair
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批准号:8184287
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项目类别:
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资助金额:$28.78万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
AF AND AAF MODIFIED DNA STRUCTURES--MUTAGENIC RELEVANCE
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批准号:2896157
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项目类别:
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资助金额:$15.95万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
Aromatic Amine-DNA Lesions: Mutagenicity and Repair
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批准号:8677708
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项目类别:
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资助金额:$28.1万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
Aromatic Amine-DNA Lesions: Mutagenicity and Repair
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批准号:8274634
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项目类别:
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资助金额:$28.77万
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财政年份:1997
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负责人:Suse Broyde
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依托单位:
海外基金