Insight into the mechanism of action of the SSB interactome
深入了解 SSB 相互作用组的作用机制
基本信息
- 批准号:10574583
- 负责人:
- 金额:$ 31.19万
- 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:2022-02-16 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityBRCA2 geneBindingBinding ProteinsBiochemistryBiological AssayBiological ModelsBiologyC-terminal binding proteinCaringCell DeathComplexCreativenessCryoelectron MicroscopyCrystallographyDNADNA BindingDNA biosynthesisDNA metabolismDNA-Binding ProteinsDNA-Directed DNA PolymeraseDataDefectDevelopmentDisparateElementsEnzyme KineticsEscherichia coliEukaryotaEventFamilyFamily memberFosteringGeneticGenetic RecombinationGenomeGenome StabilityGoalsHealthIn VitroKineticsLeadLengthMaintenanceMalignant NeoplasmsMediatingMissionMolecularMultiple PartnersMutationOligonucleotidesOligosaccharidesOrganismOutcomePlayProkaryotic CellsProteinsPublic HealthPublishingReactionReplication-Associated ProcessResearchRoleSS DNA BPSingle-Stranded DNAStructureSystemTailTestingTimeUnited States National Institutes of HealthWorkcombinatorialgenome integrityhelicasehuman diseaseimprovedin vivoinnovationinsightmembernovelprotein Bprotein functionpublic health relevancerepairedsingle moleculesuperresolution microscopy
项目摘要
ABSTRACT
The single-stranded DNA binding protein (SSB) is the founding member of the nineteen-partner SSB interactome. There is
a fundamental gap in understanding the mechanism of action of the interactome, the first prokaryotic family of
oligosaccharide/oligonucleotide binding fold (OB-fold) genome guardians identified. The continued existence of this gap
represents an important problem because, until it is filled, a complete and clear understanding of genome stability will be
lacking. This understanding is crucial as defects in OB-fold genome guardian family members have disastrous consequences
for genome stability. In higher organisms, mutations in the three OB-folds of BRCA2 ultimately result in cancer, and the
proposed studies are therefore directly relevant to human disease. Consequently, the long-term goal is to understand the
molecular mechanism of the SSB interactome. The main objective of this proposal is to understand how SSB interacts with,
and regulates, several partner proteins and itself, to maintain genome integrity. The central hypothesis is that two regions
of SSB known as the linker and the OB-fold, (present in both SSB and interactome partners), are the key elements to all
aspects of protein function. The rationale for the proposed research is that once it is known how SSB physically and
functionally interacts with both itself and its partners, a clearer understanding of the events required to maintain genome
integrity, mediated by this OB-fold family of genome guardians, will be obtained. The central hypothesis will be tested by
pursuing two specific aims: 1) determine the role of the linker/OB-fold network in SSB function; and 2) determine the
mechanism of action of the SSB interactome. Under the first aim, a combination of in vivo and in vitro binding assays,
HDX-MS, protein crystallography, cryo-EM, and single-molecule biochemistry will be used to determine whether the
linker/OB-fold interface is the primary means of SSB-partner binding. Under the second aim, enzyme kinetics, genetics,
real-time super-resolution microscopy, and single-molecule biochemistry will be used to understand how the linker/OB-
fold network mediates SSB interactome function in the dynamic reactions of DNA replication, recombination, and repair.
The proposed research is innovative because of the combinatorial strategy taken, the novel single-molecule approaches
used, and the care that we will take in elucidating SSB interactome function using full-length proteins. The proposed
research is significant because it will allow, for the first time, the development of a clear picture of SSB interactome function
in DNA metabolism and the maintenance of genome integrity.
摘要
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ram I. Mahato其他文献
Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems
寡核苷酸疗法与递送系统的药学视角
- DOI:
10.1016/j.pharmr.2025.100065 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:17.300
- 作者:
Dalton W. Staller;Flobater I. Gawargi;Sanjali S. Panigrahi;Paras K. Mishra;Ram I. Mahato - 通讯作者:
Ram I. Mahato
nbsp;Doxorubicin and Lapatinib Combination Nanomedicine for Treating Resistant Breast Cancer
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:4.9
- 作者:
Chengan Du;Huixin Wang;Ram I. Mahato;Yongzhuo Huang - 通讯作者:
Yongzhuo Huang
Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA
- DOI:
10.1007/s11095-011-0608-1 - 发表时间:
2011-10-28 - 期刊:
- 影响因子:4.300
- 作者:
Saurabh Singh;Ajit S. Narang;Ram I. Mahato - 通讯作者:
Ram I. Mahato
 Doxorubicin and Lapatinib Combination Nanomedicine for Treating Resistant Breast Cancer
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:
- 作者:
Chengan Du;Huixin Wang;Ram I. Mahato;Yongzhuo Huang; - 通讯作者:
COG133 peptide-conjugated lipid nanoparticles sensitize medulloblastoma to radiation therapy in mice
COG133肽偶联脂质纳米粒使小鼠髓母细胞瘤对放射治疗敏感
- DOI:
10.1016/j.jconrel.2025.113902 - 发表时间:
2025-08-10 - 期刊:
- 影响因子:11.500
- 作者:
Aditya Gupta;Sohan Mahto;Rebecca E. Oberley Deegan;Donald W. Coulter;Ram I. Mahato - 通讯作者:
Ram I. Mahato
Ram I. Mahato的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ram I. Mahato', 18)}}的其他基金
Development and Preclinical Evaluation of Nanoformulations in Liver Fibrotic Mice
肝纤维化小鼠纳米制剂的开发和临床前评价
- 批准号:
10639037 - 财政年份:2023
- 资助金额:
$ 31.19万 - 项目类别:
Lipid nanomedicine targeting multiple signaling pathways of medulloblastoma
靶向髓母细胞瘤多种信号通路的脂质纳米药物
- 批准号:
10663377 - 财政年份:2022
- 资助金额:
$ 31.19万 - 项目类别:
Nanomedicine of Hedgehog and AKT/ERK Dual Inhibitors for Pancreatic Cancer
Hedgehog和AKT/ERK双重抑制剂治疗胰腺癌的纳米药物
- 批准号:
10346555 - 财政年份:2022
- 资助金额:
$ 31.19万 - 项目类别:
Lipid nanomedicine targeting multiple signaling pathways of medulloblastoma
靶向髓母细胞瘤多种信号通路的脂质纳米药物
- 批准号:
10504006 - 财政年份:2022
- 资助金额:
$ 31.19万 - 项目类别:
Nanomedicine of Hedgehog and AKT/ERK Dual Inhibitors for Pancreatic Cancer
Hedgehog和AKT/ERK双重抑制剂治疗胰腺癌的纳米药物
- 批准号:
10555244 - 财政年份:2022
- 资助金额:
$ 31.19万 - 项目类别:
Research and Development of Novel Drug Delivery Systems Symposium
新型给药系统研发研讨会
- 批准号:
8907150 - 财政年份:2015
- 资助金额:
$ 31.19万 - 项目类别:
Polymeric Nanomedicines of Small Molecules and miRNA for Treating Pancreatic Canc
用于治疗胰腺癌的小分子和 miRNA 聚合纳米药物
- 批准号:
9298650 - 财政年份:2014
- 资助金额:
$ 31.19万 - 项目类别:
Polymeric Nanomedicines of Small Molecules and miRNA for Treating Pancreatic Canc
用于治疗胰腺癌的小分子和 miRNA 聚合纳米药物
- 批准号:
8761405 - 财政年份:2014
- 资助金额:
$ 31.19万 - 项目类别:
Targeted Delivery of TFOs for Treatment of Liver Fibrosis
TFO 靶向递送治疗肝纤维化
- 批准号:
7212732 - 财政年份:2007
- 资助金额:
$ 31.19万 - 项目类别:
Targeted Delivery of TFOs for Treatment of Liver Fibrosis
TFO 靶向递送治疗肝纤维化
- 批准号:
7359615 - 财政年份:2007
- 资助金额:
$ 31.19万 - 项目类别:
相似海外基金
The role of the BRCA1 and BRCA2 gene in the pathogenesis
BRCA1和BRCA2基因在发病机制中的作用
- 批准号:
7315995 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
BRCA1 and BRCA2 gene in breast cancer pathogenesis
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
6988627 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis
BRCA1和BRCA2基因在发病机制中的作用
- 批准号:
6830360 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
7594304 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
10020051 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
9152707 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
Role of BRCA1/BRCA2 gene in pathogenesis of breat cancer
BRCA1/BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
6556003 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
8349977 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
7734867 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别:
The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer
BRCA1和BRCA2基因在乳腺癌发病机制中的作用
- 批准号:
8750661 - 财政年份:
- 资助金额:
$ 31.19万 - 项目类别: