Project 2: Error-free and Mutagenic Processing of Crosslinks
项目 2:交联的无差错和诱变处理
基本信息
- 批准号:9148675
- 负责人:
- 金额:$ 34.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-10 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAntineoplastic AgentsBiochemicalBiological AssayBypassCancer EtiologyCancer PatientCarcinogensCell LineCell SurvivalCellsChinese Hamster Ovary CellDNADNA DamageDNA Double Strand BreakDNA Interstrand CrosslinkingDNA RepairDNA analysisDNA-protein crosslinkDeoxyribonucleasesDevelopmentDiseaseDouble Strand Break RepairERCC1 geneEnzymesEtiologyExcisionExposure toFamily memberFanconi&aposs AnemiaGeneticGenetic EngineeringGenetic RecombinationGenomeGoalsHMGB1 geneHMGB2 geneHMGB3 geneHigh Mobility Group ProteinsHumanInvestigationKnowledgeLesionMalignant NeoplasmsMammalian CellMetabolismMismatch RepairMolecularMutagenesisMutationNucleotide Excision RepairOutcomeParticipantPathologic MutagenesisPathway interactionsPatient-Focused OutcomesProcessProteinsPublic HealthRecruitment ActivityReporterResearchRoleRouteSecond Primary CancersShuttle VectorsSiteStructureSurgical incisionsTestingWorkXPA geneanti-cancer therapeuticbasechemotherapeutic agentchemotherapycrosslinkexperimental studyhomologous recombinationin vivoinnovationmammalian genomemutantnovelnovel strategiesnucleaseprogramsrepair enzymerepairedscaffold
项目摘要
PROJECT SUMMARY
DNA interstrand crosslinks (ICLs) present formidable blocks to DNA metabolic processes and must be repaired
for cell survival. Because ICLs are so toxic, many ICL-inducing agents are used as anticancer therapeutics.
The use of such chemotherapeutic agents can also result in the formation of DNA-protein crosslinks (DPCs).
While proteins from several repair pathways are thought to be involved in processing ICLs and DPCs, the
mechanisms of ICL and DPC repair in mammalian cells are not clearly defined. Thus, the overall goal of the
proposed studies is to fill this gap in knowledge by elucidating the mechanisms of crosslink repair in
mammalian cells. We and others have demonstrated that proteins from several repair pathways are involved in
ICL repair, including nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination
(HR), Fanconi anemia (FA), and high mobility group (HMGB) proteins. However, their functions and
interactions in ICL repair in mammalian cells are not well understood. The novel hypotheses to be tested are
that: ERCC1-XPF is involved in the initial unhooking of ICLs in an SLX4- or UHRF1-dependent fashion; that
HMGB1, but not HMGB3, is involved in the recruitment of ERCC1-XPF to ICLs to facilitate unhooking in an
SLX4-independent fashion; and that ICL-induced DSBs are processed by mutagenic and error-free HR
pathways, specifically regulated by HMGB proteins in mammalian cells. The long-term objectives are to
elucidate molecular mechanisms involved in the removal of crosslinks from the mammalian genome.
Specifically we propose to: (a) determine in vivo the mechanisms of incision and mutagenesis during crosslink
repair; (b) elucidate the mechanisms involved in error-free and mutagenic crosslink repair associated with ICL-
induced DSB formation; and (c) determine the mutagenic and recombinogenic impact of DPCs in human cells.
The proposed work is innovative because it will test novel hypotheses; moreover, a unique feature of the
approach is to induce site-specific ICLs in mammalian genomes to study their repair. In addition, genetically
engineered mammalian cells lines constructed for this project will allow for definitive assessment of the roles of
repair proteins in ICL processing in vivo, by separating the initial unhooking steps from the subsequent DSB-
induced HR processing. These experiments will define the function of novel components (e.g. UHRF1 and
HMGB proteins) involved in ICL repair, and have the potential to identify as yet undetermined
proteins/pathways involved in the repair of crosslinks. The expected contribution is that the mechanisms of ICL
and DPC repair in mammalian cells will be elucidated, which is significant because the new information
obtained will aid in the development of novel targeted strategies to control human cancers using crosslinking
agents. The studies will also contribute significant fundamental new knowledge to the fields of genetic
instability and DNA damage and repair.
项目摘要
DNA链间交联(ICLs)是DNA代谢过程的障碍,必须修复
for cell细胞survival生存.由于ICL毒性很大,许多ICL诱导剂被用作抗癌治疗剂。
使用这样的化疗剂也可以导致DNA-蛋白质交联(DPC)的形成。
虽然来自几种修复途径的蛋白质被认为参与了ICL和DPC的加工,但这些蛋白质可能与ICL和DPC有关。
哺乳动物细胞中ICL和DPC修复的机制尚未明确定义。因此,
提出的研究是通过阐明交联修复的机制来填补这一知识空白,
哺乳动物细胞我们和其他人已经证明,来自几个修复途径的蛋白质参与了
ICL修复,包括核苷酸切除修复(NER)、错配修复(MMR)、同源重组
(HR)Fanconi贫血(FA)和高迁移率族(HMGB)蛋白。然而,其功能和
在哺乳动物细胞中ICL修复的相互作用还没有很好地理解。待检验的新假设是
ERCC 1-XPF以SLX 4或UHRF 1依赖的方式参与ICL的初始脱钩;
HMGB 1,而不是HMGB 3,参与ERCC 1-XPF向ICL的募集,以便于在一个特定的时间段内脱钩。
SLX 4-独立的方式; ICL诱导的DSB由致突变和无错误的HR处理
在哺乳动物细胞中由HMGB蛋白特异性调节。长期目标是
阐明从哺乳动物基因组中去除交联所涉及的分子机制。
具体而言,我们建议:(a)确定在体内的切割和诱变交联过程中的机制
修复;(B)阐明与ICL相关的无错误和致突变交联修复中涉及的机制。
诱导的DSB形成;和(c)确定DPC在人细胞中的致突变和重组影响。
拟议的工作是创新的,因为它将测试新的假设;此外,
方法是在哺乳动物基因组中诱导位点特异性ICL以研究其修复。此外,从基因上
为该项目构建的工程化哺乳动物细胞系将允许明确评估
通过将初始脱钩步骤与随后的DSB分离,
诱导HR处理。这些实验将定义新组分(例如UHRF 1和
HMGB蛋白)参与ICL修复,并有可能识别尚未确定的
参与交联修复的蛋白质/途径。预期的贡献是,
和DPC修复在哺乳动物细胞将阐明,这是重要的,因为新的信息
将有助于开发新的靶向策略,以控制人类癌症,
剂.这些研究还将为遗传学领域提供重要的基础新知识,
不稳定性和DNA损伤和修复。
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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Karen M Vasquez其他文献
DNA interstrand crosslinks: Repair, cell signaling, and therapeutic implications
DNA 链间交联:修复、细胞信号传导和治疗意义
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:2.8
- 作者:
Karen M Vasquez;R. Legerski - 通讯作者:
R. Legerski
Karen M Vasquez的其他文献
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{{ truncateString('Karen M Vasquez', 18)}}的其他基金
Impact of Short Inverted Repeats on Genetic Instability at Mutation Hotspots
短反向重复序列对突变热点遗传不稳定性的影响
- 批准号:
8756978 - 财政年份:2014
- 资助金额:
$ 34.09万 - 项目类别:
Impact of Short Inverted Repeats on Genetic Instability at Mutation Hotspots
短反向重复序列对突变热点遗传不稳定性的影响
- 批准号:
8889235 - 财政年份:2014
- 资助金额:
$ 34.09万 - 项目类别:
Recognition and processing of complex lesions by components from multiple DNA
通过多种 DNA 成分识别和处理复杂病变
- 批准号:
8403932 - 财政年份:2004
- 资助金额:
$ 34.09万 - 项目类别:
Processing Site-Specific DNA Lesions by DNA Repair/Recom
通过 DNA 修复/重组处理位点特异性 DNA 损伤
- 批准号:
6990365 - 财政年份:2004
- 资助金额:
$ 34.09万 - 项目类别:
Recognition and processing of complex lesions by components from multiple DNA
通过多种 DNA 成分识别和处理复杂病变
- 批准号:
7781951 - 财政年份:2004
- 资助金额:
$ 34.09万 - 项目类别:
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