Investigation of Intercalated (I) Motif DNA Structure at Telomeric Cytosine-Rich Strand in Human Cells Genetically Altered for DNA Helicases
对 DNA 解旋酶基因改变的人类细胞中端粒富含胞嘧啶链插入 (I) 基序 DNA 结构的研究
基本信息
- 批准号:10913185
- 负责人:
- 金额:$ 5.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdenineAntibodiesApoptosisBase PairingBindingBiochemicalBiologicalCell AgingCell Cycle ArrestCell DeathCell LineCellsCentromereChromosomesClustered Regularly Interspaced Short Palindromic RepeatsComputational algorithmCytosineDNADNA DamageDNA Polymerase IDNA SequenceDNA StructureDNA biosynthesisDNA-Directed DNA PolymeraseDetectionEnzyme InteractionEscherichia coliFiberG-QuartetsGene ExpressionGenesGenomicsGuanineHumanHuman GenomeImmunofluorescence ImmunologicIn VitroInvestigationKnock-outLigandsMetabolic PathwayMetabolismMolecularPhenotypePromoter RegionsProteinsReagentRecombinantsRegulationReportingResearchResolutionStructureTERF1 geneTechniquesTelomeraseTestingThymineWorkcancer therapycarboxylatecarboxylationcell typechemical bondexperimental studyhelicasein vivointercalationmutantnovelpharmacologicpreservationpreventpromoterresponsesenescencesingle walled carbon nanotubeskillssmall moleculetelomere
项目摘要
The I-motif is a cytosine-rich DNA sequence that forms a non-canonical DNA structure deviating from the conventional chemical bonding rules that dictate the three-dimensional arrangement of the DNA double helix with strict complementary base pairing (adenine (A): thymine (T); guanine (G): cytosine (C)) and a defined stacking arrangement of the base pairs (bps). Instead, the I-motif forms two intercalated parallel-stranded duplexes held together by hemi-protonated C-C bps. Analysis of the human genome by the computer algorithm Quadparser identified 5,125 DNA sequences that can fold into I-motif structures (also designated C-quadruplex or C4). Most of these C-rich sequences predicted to form C4 are found in telomeres, centromeres, and gene promoter regions.
Regulation of genomic I-motif DNA structure is a potential mechanism to modulate gene expression or telomere metabolism with implications for cancer therapy, cellular senescence and aging. Carboxylated single-walled carbon nanotubes (SWNTs) were the first ligand found to selectively stabilize human telomeric I-motif DNA structures, thereby inhibiting telomeric repeat synthesis by telomerase in vitro and in human cells. I-motif stabilization by SWNTs resulted in telomere uncapping and induced a telomeric DNA damage response that led to cell cycle arrest, senescence or apoptosis. Recently, small molecules (in the NCI Diversity Set) were discovered that specifically bind I-motif DNA structures and stabilize them (NSC 1389484 ; NSC 3098745) or bind to the C-rich hairpin, thereby preventing C4 formation (NSC 592764; NSC 1463976). While these compounds were tested for their effects on gene promoter activity, their impact on telomere metabolism was either not addressed or reported.
Despite experimental evidence that C4 DNA structures form in vivo and exert unique biological consequences, their molecular metabolic pathways are poorly understood. For example, while work from our lab and others demonstrated that specialized DNA helicases have been characterized for their vital functions to resolve G-quadruplex (G4) DNA formed by G-rich sequences in the human genome, there are no reports that helicase enzymes interact with or catalytically unwind I-motif quadruplexes. Moreover, there have been no studies detailing the effects of I-motif DNA structures on replication in vivo; however, one in vitro study demonstrated that DNA synthesis by the E. coli DNA polymerase fragment Klenow was stalled by a I-motif DNA structure.
i基序是一个富含胞嘧啶的DNA序列,它形成了一个非规范的DNA结构,偏离了传统的化学键规则,这种规则规定了DNA双螺旋的三维排列,具有严格的互补碱基配对(腺嘌呤(a):胸腺嘧啶(T);鸟嘌呤(G):胞嘧啶(C))和碱基对(bps)的确定堆叠排列。相反,i基序形成两个插入的平行链双链,由半质子化的C-C bps连接在一起。通过计算机算法Quadparser对人类基因组进行分析,鉴定出5125个可以折叠成i基序结构(也称为c -四plex或C4)的DNA序列。大多数预测形成C4的富含c的序列存在于端粒、着丝粒和基因启动子区域。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Robert Brosh其他文献
Robert Brosh的其他文献
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{{ truncateString('Robert Brosh', 18)}}的其他基金
Molecular Characterization of the SARS-CoV-2 Helicase and High-Throughput Screening to Identify Small Molecule SARS-CoV-2 Helicase Inhibitors as Anti-Viral Medicines
SARS-CoV-2 解旋酶的分子表征和高通量筛选以鉴定小分子 SARS-CoV-2 解旋酶抑制剂作为抗病毒药物
- 批准号:
10251673 - 财政年份:
- 资助金额:
$ 5.7万 - 项目类别:
Molecular Characterization of the SARS-CoV-2 Helicase and High-Throughput Screening to Identify Small Molecule SARS-CoV-2 Helicase Inhibitors as Anti-Viral Medicines
SARS-CoV-2 解旋酶的分子表征和高通量筛选以鉴定小分子 SARS-CoV-2 解旋酶抑制剂作为抗病毒药物
- 批准号:
10913114 - 财政年份:
- 资助金额:
$ 5.7万 - 项目类别:
Function of RecQ helicases in genome stability
RecQ 解旋酶在基因组稳定性中的功能
- 批准号:
10913133 - 财政年份:
- 资助金额:
$ 5.7万 - 项目类别:
Roles Of DNA Helicases In Pathways Required For Maintenance Of Genomic Stability
DNA 解旋酶在维持基因组稳定性所需途径中的作用
- 批准号:
8148305 - 财政年份:
- 资助金额:
$ 5.7万 - 项目类别:
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