Translesion synthesis DNA polymerases and genome instability
跨损伤合成 DNA 聚合酶和基因组不稳定性
基本信息
- 批准号:10428486
- 负责人:
- 金额:$ 33.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgeAge FactorsAlkylating AgentsBypassCaringCell divisionCell modelCellsCharacteristicsChildbirthComplexCongenital DisordersDNADNA DamageDNA StructureDNA biosynthesisDNA polymerase zetaDNA replication forkDNA-Directed DNA PolymeraseDataDefectDevelopmentDiseaseDrug usageEnvironmental ExposureEnvironmental ImpactEnvironmental Risk FactorEnzymesEukaryotic CellEventExposure toFamilial colorectal cancerFamilyFolic Acid AntagonistsFolic Acid DeficiencyFrequenciesFundingFuture GenerationsGametogenesisGenerationsGenesGenomic InstabilityGerm-Line MutationGrantHereditary DiseaseHumanIncidenceIndividualInheritedKnowledgeLeadLesionLifeLinkMalignant NeoplasmsMediatingMedicalMeiosisMethyl MethanesulfonateMitoticModelingMusMutagenesisMutationMutation DetectionMutation SpectraOnset of illnessOrganismParental AgesParentsPathogenicityPathway interactionsPatientsPolymerasePopulationPrevention strategyProcessPublic HealthRecurrenceReportingRoleSamplingSocietiesSomatic CellSomatic MutationSourceSpecificitySpermatocytesStructureSusceptibility GeneSyndromeSystemTestingTherapeuticVariantWorkYeast Model SystemYeastscancer predispositiondefined contributiondetection assaydietaryearly onseteggenvironmental mutagensenvironmental stressorexperimental studyhomologous recombinationhydroxyureain vivoinhibitormouse modelnext generationnovelpolyposisrecruitreplication stressreproductivesperm cell
项目摘要
Abstract
This competitive renewal application seeks to investigate the role of translesion synthesis DNA polymerases in
mutagenesis associated with meiotic cell divisions. Unlike somatic mutations that only impact the individual,
DNA changes occurring during meiosis are transmitted to the next generations and lead to the development of
hereditary diseases. With the childbirth age steadily increasing over the past decades, the frequency of de
novo germline mutations in the human population has continuously been on the rise. The resulting hereditary
diseases present a significant burden for the individuals, families and the society, since the patients often
develop multiple medical problems at an early age and require specialized life-long care. The mechanisms
responsible for the generation of germline mutations are poorly understood, as nearly all mechanistic studies of
mutagenesis employ mitotic cells. In the previous cycles of this grant, we discovered and explored a novel
mutagenesis pathway wherein error-prone DNA polymerase ζ (Polζ) is recruited to DNA replication forks
stalled at small hairpin DNA structures and facilitates the bypass of these structures, producing a characteristic
mutational signature. This pathway is silent in healthy mitotic cells because the robust normal replication
machinery is not significantly impeded by the small secondary structures. The Polζ-dependent error-prone
structure bypass, however, becomes a factor when intrinsic or environmental stressors promote fork stalling.
Unexpectedly, our preliminary data suggested that this pathway is also activated during normal meiosis and is
a likely source of recurrent germline mutations in cancer predisposition genes. We will test this hypothesis by
pursuing three Specific Aims. In Aim 1, we will define the contribution of the Polζ-dependent pathway to
germline- and meiosis-specific mutagenesis. In Aim 2, we will use the human POLE gene linked to a hereditary
colorectal cancer predisposition syndrome as a model to identify meiosis-specific hotspots of mutagenesis and
define their relationship to Polζ-dependent hairpin bypass. In Aim 3, we will determine the effects of
environmental DNA damaging agents and replication inhibitors on the accumulation of Polζ-dependent
mutations during gametogenesis. Yeast, mouse and human cell models will be used in these studies, with the
yeast system providing the most power for mechanistic analysis, the mouse providing the opportunity to
experimentally study mutagenesis during mammalian meiosis in vivo, and the data on human samples
establishing the ultimate link to disease. We expect to gain new fundamental knowledge on the mechanism of
mutagenesis in the germline that impacts future generations. We also expect to understand the reasons for
frequent de novo formation of some disease-causing germline variants and the effects of environmental
factors.
摘要
该竞争性更新申请旨在研究跨损伤合成DNA聚合酶在细胞内的作用。
与减数分裂细胞分裂有关的诱变。与只影响个体的体细胞突变不同,
减数分裂期间发生的DNA变化传递给下一代并导致
遗传性疾病在过去的几十年里,随着生育年龄的稳步增长,
人类中的新生生殖系突变一直在不断增加。由此产生的遗传
疾病给个人、家庭和社会带来了巨大的负担,因为患者经常
在很小的时候就出现多种医疗问题,需要专门的终身护理。的机制
对生殖系突变产生的原因知之甚少,因为几乎所有关于生殖系突变的机制研究,
诱变使用有丝分裂细胞。在前几轮的资助中,我们发现并探索了一部小说,
诱变途径,其中易错的DNA聚合酶P13(Pol P13)被募集到DNA复制叉
停滞在小发夹DNA结构,并促进绕过这些结构,产生一种特征
突变特征这一途径在健康的有丝分裂细胞中是沉默的,
小的次级结构不会显著阻碍机械。Pol依赖的易错
然而,当内在或环境压力源促进分叉失速时,结构旁路成为一个因素。
出乎意料的是,我们的初步数据表明,这一途径也在正常减数分裂过程中被激活,
癌症易感基因中生殖细胞突变的可能来源。我们将通过以下方式检验这一假设:
追求三个具体目标。在目标1中,我们将定义Pol β依赖性途径对
生殖系和减数分裂特异性诱变。在目标2中,我们将使用人类POLE基因与遗传性
结直肠癌易感综合征作为鉴定减数分裂特异性诱变热点的模型,
定义它们与依赖于Pol β的发夹旁路的关系。在目标3中,我们将确定
环境DNA损伤剂和复制抑制剂对聚合酶依赖性
配子发生过程中的突变酵母、小鼠和人细胞模型将用于这些研究,
酵母系统为机械分析提供了最大的动力,小鼠提供了
实验研究哺乳动物体内减数分裂过程中的诱变,以及人类样本的数据
建立与疾病的终极联系。我们期望获得新的基础知识的机制,
影响后代的种系突变。我们还希望了解
一些致病生殖系变异的频繁从头形成以及环境因素的影响,
因素
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)
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Polina V Shcherbakova其他文献
Polina V Shcherbakova的其他文献
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{{ truncateString('Polina V Shcherbakova', 18)}}的其他基金
Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations
DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制
- 批准号:
9917394 - 财政年份:2019
- 资助金额:
$ 33.79万 - 项目类别:
Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations
DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制
- 批准号:
10750422 - 财政年份:2019
- 资助金额:
$ 33.79万 - 项目类别:
Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations
DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制
- 批准号:
10543990 - 财政年份:2019
- 资助金额:
$ 33.79万 - 项目类别:
Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations
DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制
- 批准号:
10524176 - 财政年份:2019
- 资助金额:
$ 33.79万 - 项目类别:
Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations
DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制
- 批准号:
10307149 - 财政年份:2019
- 资助金额:
$ 33.79万 - 项目类别:
Mechanisms of Genome Instability in Tumors with DNA Polymerase Epsilon Mutations
DNA 聚合酶 Epsilon 突变肿瘤中基因组不稳定性的机制
- 批准号:
10066328 - 财政年份:2019
- 资助金额:
$ 33.79万 - 项目类别:
Translesion Synthesis DNA Polymerases and Genome Instability
跨损伤合成 DNA 聚合酶和基因组不稳定性
- 批准号:
8272580 - 财政年份:2009
- 资助金额:
$ 33.79万 - 项目类别:
Translesion Synthesis DNA Polymerases and Genome Instability
跨损伤合成 DNA 聚合酶和基因组不稳定性
- 批准号:
8463180 - 财政年份:2009
- 资助金额:
$ 33.79万 - 项目类别:
Translesion Synthesis DNA Polymerases and Genome Instability
跨损伤合成 DNA 聚合酶和基因组不稳定性
- 批准号:
8860181 - 财政年份:2009
- 资助金额:
$ 33.79万 - 项目类别:
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