PROJECT 3
项目3
基本信息
- 批准号:9804093
- 负责人:
- 金额:$ 32.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-09 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:2&apos-DeoxythymidineAPOBEC3F geneAchievementActive SitesAddressAdjuvantAffinityBindingBiological AssayC-terminalCCL21 geneCancer EtiologyCatalytic DomainCellsChemicalsClinicalClosure by clampComplexComputer SimulationCrystallizationCytosineDNADNA BindingDNA DamageDNA RepairDNA SequenceDNA biosynthesisDataDeaminaseDeaminationDeoxycytidineDevelopmentDiagnosisDinucleoside PhosphatesDiseaseDrug resistanceEnzymesEstrogen receptor positiveEvolutionFamilyFamily memberFoundationsFutureGTP-Binding Protein alpha Subunits, GsGenomeGenomicsGoalsHistidineHumanIn VitroInnate Immune ResponseKnowledgeLengthLifeMalignant NeoplasmsMediatingMolecularMolecular ChaperonesMolecular ConformationMonoclonal AntibodiesMutagenesisMutationN-terminalNeoplasm MetastasisOutcomePathogenicityPatient-Focused OutcomesPositioning AttributeProcessProtein EngineeringProteinsPublishingRNAResearchResidual stateResistanceResolutionRoentgen RaysRoleSingle-Stranded DNASolidSourceSpecificityStructureSystemTamoxifenTestingThymineUracilVariantVertebral columnVirusWorkactivation-induced cytidine deaminaseanalogapoB mRNA editing catalytic subunitbasecancer therapydrug developmentds-DNAgenetic regulatory proteinimprovedin vivoinhibitor/antagonistmalignant breast neoplasmmembermouse modelnovelnucleobaseoverexpressionpreferencepreventprogramsstructural biologytherapeutic targettherapy outcometumortumor heterogeneity
项目摘要
PROJECT 3 – STRUCTURAL BIOLOGY OF DNA DEAMINASES IN BREAST CANCER
ABSTRACT
The hallmark activity of the APOBEC family of enzymes is deamination of cytosines to uracils (C-to-U) in
single-stranded (ss)DNA. This editing activity normally functions in the innate immune response by contributing
to virus and transposon restriction. However, recent studies by our labs and many others strongly indicate that
APOBEC3B (A3B) is a major source of genomic mutations that drive the progression of multiple human
cancers and the development of drug resistance. This finding – that a cellular enzyme actively introduces
mutations in cancer – is in stark contrast to a more conventional view, in which mutations in cancer are caused
by DNA damage from exogenous sources or errors introduced during DNA replication or repair. Because A3B
is not an essential enzyme for life, it is a promising target for anti-cancer therapies. Thus, our Program's
overarching hypothesis is that A3B inhibition, as an adjuvant to primary treatment options, will help to prevent
detrimental mutation-driven outcomes such as drug resistance and metastasis. However, despite its strong
relevance to cancer as a potential therapeutic target, it is not fully known how A3B engages ssDNA substrates,
how it achieves high selectivity for ssDNA over RNA, or how its DNA deaminase activity is regulated in cells.
Moreover, it is not known how related enzymes such as APOBEC3H (A3H) and APOBEC3F (A3F) with
different compositions of ssDNA-binding residues engage similar target sequences. In Project 3, we have
started to address these issues by solving multiple A3B catalytic domain crystal structures and, recently,
achieving co-crystal structures of ssDNA bound to a variant of the A3B catalytic domain as well as to the
related enzyme APOBEC3A (A3A). Aim 1 will build on this knowledge to further delineate the global ssDNA
binding mechanism of A3B and A3H. Aim 2 will examine the local dinucleotide targeting mechanism and
possible modes of inhibition of the APOBEC family of enzymes. Our goals are to gain deeper mechanistic
understandings of the pathogenic APOBEC-mediated ssDNA cytosine deamination process and to establish a
solid foundation for future development of APOBEC inhibitors for cancer therapies. These studies will propel
our Program toward achieving its long-term goal of inhibiting APOBEC mutagenesis in breast cancer, thereby
slowing tumor evolution and improving overall therapeutic outcomes for patients.
项目 3 – 乳腺癌 DNA 脱氨酶的结构生物学
抽象的
APOBEC 酶家族的标志性活性是胞嘧啶脱氨基为尿嘧啶(C-to-U)
单链(ss)DNA。这种编辑活动通常通过贡献在先天免疫反应中发挥作用
病毒和转座子限制。然而,我们实验室和许多其他实验室最近的研究强烈表明
APOBEC3B (A3B) 是驱动多种人类疾病进展的基因组突变的主要来源
癌症和耐药性的发展。这一发现——细胞酶主动引入
癌症突变——与癌症突变引起的更传统观点形成鲜明对比
由于外源性 DNA 损伤或 DNA 复制或修复过程中引入的错误。因为A3B
虽然不是生命必需的酶,但它是抗癌治疗的一个有前景的靶标。因此,我们的计划的
总体假设是 A3B 抑制作为主要治疗方案的辅助剂,将有助于预防
有害的突变驱动的结果,例如耐药性和转移。然而,尽管其实力雄厚
与癌症作为潜在治疗靶点的相关性,目前尚不完全清楚 A3B 如何与 ssDNA 底物结合,
它如何实现对 ssDNA 相对于 RNA 的高选择性,或者如何在细胞中调节其 DNA 脱氨酶活性。
此外,尚不清楚 APOBEC3H (A3H) 和 APOBEC3F (A3F) 等酶与
ssDNA 结合残基的不同组成与相似的靶序列结合。在项目 3 中,我们有
开始通过解决多个 A3B 催化域晶体结构来解决这些问题,最近,
实现 ssDNA 与 A3B 催化结构域变体以及
相关酶 APOBEC3A (A3A)。目标 1 将以此知识为基础,进一步描绘全球 ssDNA
A3B和A3H的结合机制。目标 2 将检查局部二核苷酸靶向机制并
APOBEC 酶家族的可能抑制模式。我们的目标是获得更深层次的机制
了解致病性 APOBEC 介导的 ssDNA 胞嘧啶脱氨过程并建立一个
为未来开发用于癌症治疗的 APOBEC 抑制剂奠定了坚实的基础。这些研究将推动
我们的计划旨在实现抑制乳腺癌 APOBEC 突变的长期目标,从而
减缓肿瘤演变并改善患者的整体治疗结果。
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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Hideki Aihara其他文献
Hideki Aihara的其他文献
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{{ truncateString('Hideki Aihara', 18)}}的其他基金
Project 4: Nuclease Inhibitors for Viruses of Pandemic Concern
项目 4:针对流行病病毒的核酸酶抑制剂
- 批准号:
10522813 - 财政年份:2022
- 资助金额:
$ 32.03万 - 项目类别:
Structural studies of viral replication and invasion
病毒复制和侵袭的结构研究
- 批准号:
10337889 - 财政年份:2016
- 资助金额:
$ 32.03万 - 项目类别:
Structural studies of viral replication and invasion
病毒复制和侵袭的结构研究
- 批准号:
10544179 - 财政年份:2016
- 资助金额:
$ 32.03万 - 项目类别:
Crystallographic studies of retroviral intasome complexes
逆转录病毒嵌体复合物的晶体学研究
- 批准号:
8919420 - 财政年份:2014
- 资助金额:
$ 32.03万 - 项目类别:
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