The role of And-1 in nucleotide excision repair
And-1在核苷酸切除修复中的作用
基本信息
- 批准号:10362967
- 负责人:
- 金额:$ 45.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-17 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAnimal ModelBindingCell CycleCellsChromosomal StabilityComplementDBL OncoproteinDNA DamageDNA RepairDNA biosynthesisDNA lesionDNA-Binding ProteinsDNA-Directed DNA PolymeraseDataDermalExcision RepairFibroblastsFutureGenesGenomeGenome StabilityHypersensitivityKnowledgeLesionLigationLinkMalignant NeoplasmsMammalsMediatingMolecularMusMutateMutationNuclearNucleotide Excision RepairNucleotidesOrthologous GenePathway interactionsPatientsPhosphorylationPhysiologicalPlayPolymerasePositioning AttributePrecision therapeuticsProcessProtein ConformationProteinsRegulationRegulatory PathwayRoleSeriesSingle-Stranded DNASiteSkinSkin CancerSkin NeoplasmsTestingTimeTranscription-Coupled RepairUV inducedUV induced DNA damageUltraviolet RaysXeroderma PigmentosumYeastschemotherapeutic agentdesignenvironmental mutagensexperimental studygene repairhomologous recombinationin vivoindividualized preventionmouse modelmultidisciplinarynovelrecombinational repairrecruitrepairedresponseskin squamous cell carcinomatherapeutic developmenttumorigenesisultraviolet irradiationultraviolet lesions
项目摘要
Project Summary
Nucleotide excision repair (NER) is the major pathway to remove bulky DNA lesions induced by UV irradiation,
environmental mutagens, and chemotherapeutic agents. Deficiency of genes involved in NER has been linked
to Xeroderma Pigmentosum (XP) and skin cancer. There are two mechanisms to detect DNA damage by NER,
one is global genome NER(GG-NER) and another is transcription-coupled NER(TC-NER). GG-NER occurs
anywhere in the genome, whereas TC-NER is responsible for the accelerated repair of lesions in the
transcribed strand of active genes. The both pathways are divided into early and late steps. The early step is
the sequential actions, in which XP proteins recognize, unwind, and incise the DNA lesion. The latter step is
identical in both mechanisms and is characterized by gap-filling repair synthesis, in which DNA replication
proteins fill in the ~30 nucleotide gap, followed by ligation. Compared to the well-characterized early step, the
molecular mechanism regulating the activation of gap-filling DNA synthesis at late step remains largely
unknown. Even less is known about the physiological impact of such a regulatory pathway.
And-1 is an acidic nucleoplasmic DNA-binding protein and its yeast ortholog, Ctf4, was originally
identified as a critical gene for chromosome stability. Interestingly, yeast cells with depletion of Ctf4 gene are
hypersensitive to UV lights, suggesting a role of And-1 in UV-induced DNA damage response. However, how
And-1 regulates NER remains largely unknown. In this study, we now have extensive preliminary data
demonstrating that And-1 is critical for NER by regulating gap-filling DNA synthesis. Our hypothesis is that
And-1 regulates DNA polymerase activity at UV-lesion sites to activate gap-filling DNA synthesis at the late
stage of NER. To test this hypothesis, we plan to pursue three specific aims. Aim 1: Determine the mechanism
by which And-1 regulates DNA polymerase activity in NER. Aim 2: Determine the unique mechanism by which
And-1 is recruited to UV-lesion sites. Aim 3: Determine the role of And-1 in NER and skin tumorigenesis using
And-1 deficient mouse models. The completion of proposed studies will not only advance the field by
uncovering a novel And-1-mediated pathway to regulate NER, but also provide us with the in vivo evidence to
elucidate a novel role of And-1 in NER and skin tumor.
项目总结
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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{{ truncateString('Wenge Zhu', 18)}}的其他基金
The role of And-1 in nucleotide excision repair
And-1在核苷酸切除修复中的作用
- 批准号:
10576346 - 财政年份:2022
- 资助金额:
$ 45.58万 - 项目类别:
Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer
靶向范可尼贫血途径克服卵巢癌铂类药物耐药性
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10392909 - 财政年份:2021
- 资助金额:
$ 45.58万 - 项目类别:
Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer
靶向范可尼贫血途径克服卵巢癌铂类药物耐药性
- 批准号:
10599218 - 财政年份:2021
- 资助金额:
$ 45.58万 - 项目类别:
Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer
靶向范可尼贫血途径克服卵巢癌铂类药物耐药性
- 批准号:
10117536 - 财政年份:2021
- 资助金额:
$ 45.58万 - 项目类别:
The Regulation of Cisplatin resistance in ovarian cancer
卵巢癌顺铂耐药的调控
- 批准号:
8916657 - 财政年份:2014
- 资助金额:
$ 45.58万 - 项目类别:
The Regulation of Cisplatin resistance in ovarian cancer
卵巢癌顺铂耐药的调控
- 批准号:
8673956 - 财政年份:2014
- 资助金额:
$ 45.58万 - 项目类别:
The Role of And-1 in DNA Damage Response
And-1 在 DNA 损伤反应中的作用
- 批准号:
9271933 - 财政年份:2014
- 资助金额:
$ 45.58万 - 项目类别:
The Regulation of Cisplatin resistance in ovarian cancer
卵巢癌顺铂耐药的调控
- 批准号:
9301488 - 财政年份:2014
- 资助金额:
$ 45.58万 - 项目类别:
The Role of And-1 in DNA Damage Response
And-1 在 DNA 损伤反应中的作用
- 批准号:
8848359 - 财政年份:2014
- 资助金额:
$ 45.58万 - 项目类别:
The Role of And-1 in DNA Damage Response
And-1 在 DNA 损伤反应中的作用
- 批准号:
8691032 - 财政年份:2014
- 资助金额:
$ 45.58万 - 项目类别:
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