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
摘要
APOBEC家族的标志性活性是胞嘧啶脱氨为尿嘧啶(C-to-U)。
单链(Ss)DNA。这种编辑活动通常在先天免疫反应中发挥作用,
病毒和转座子的限制。然而,我们的实验室和其他许多人最近的研究强烈表明
APOBEC3B(A3B)是推动多发性人类疾病进展的基因组突变的主要来源
癌症与抗药性的发展。这一发现--一种细胞酶主动地引入
癌症中的突变-与更传统的观点形成鲜明对比,在传统观点中,癌症中的突变是由
由外源造成的DNA损伤或DNA复制或修复过程中引入的错误。因为A3B
不是生命所必需的酶,它是抗癌治疗的一个很有希望的靶点。因此,我们节目的
最重要的假设是,作为主要治疗选择的辅助手段,A3B抑制将有助于预防
有害的突变驱动的结果,如耐药性和转移。然而,尽管它的强势
作为潜在的治疗靶点,A3B是如何与单链DNA底物结合的尚不完全清楚。
它如何实现对单链DNA的高选择性而不是RNA,或者它的DNA脱氨酶活性是如何在细胞中调节的。
此外,目前尚不清楚APOBEC3H(A3F)和APOBEC3H(A3F)等相关酶与
不同组成的单链DNA结合残基具有相似的靶序列。在项目3中,我们有
开始通过解决多个A3B催化结构域晶体结构来解决这些问题,最近,
获得与A3B催化结构域的变体以及与A3B催化结构域的变体结合的单链DNA的共晶结构
相关酶APOBEC3A(A3A)。目标1将在这一知识的基础上进一步描述全球单链DNA
A3B和A3H的结合机制。目标2将研究局部二核苷酸靶向机制和
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械化
对致病性APOBEC介导的单链DNA胞嘧啶脱氨过程的认识和建立
为未来癌症治疗APOBEC抑制剂的开发奠定坚实基础。这些研究将推动
我们的计划旨在实现其抑制乳腺癌APOBEC突变的长期目标,从而
减缓肿瘤演变,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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