HTLV-1 Replication/Reactivation-Induced DNA Damage: Mechanisms and Pathogenesis
HTLV-1 复制/重新激活诱导的 DNA 损伤:机制和发病机制
基本信息
- 批准号:10572907
- 负责人:
- 金额:$ 22.78万
- 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:2022-11-14 至 2024-10-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAddressAdult T-Cell Leukemia/LymphomaB lymphoid malignancyBiologicalCD4 Positive T LymphocytesCRISPR/Cas technologyCell CycleCell Cycle ArrestCell LineCell ProliferationCellsCharacteristicsChronicClonal ExpansionComplexCopy Number PolymorphismDNA DamageDNA Double Strand BreakDNA SequenceDNA cassetteDataDevelopmentEvolutionExcisionFeedbackG1/S TransitionGene CombinationsGenesGenetic TranscriptionGenomeGenomic InstabilityGenomicsHumanHuman GenomeHuman T-lymphotropic virus 1HypersensitivityIRF4 geneImmune responseIndividualInfectionLatent virus infection phaseLeucine ZippersLightLymphoma cellMalignant NeoplasmsMapsMeasuresMediatingMessenger RNAMitoticMolecularMutationNF-kappa BOncoproteinsPathogenesisPathway interactionsPersonsProcessProductivityProliferatingProvirusesRecurrenceRegulationResistanceRetroviridaeSignal TransductionSurvivorsT-Cell DevelopmentT-LymphocyteTaxesTechniquesTestingTherapeuticTimeTrans-ActivatorsTranscriptTranscription Factor AP-1Transcription-Coupled RepairTumor Suppressor ProteinsUp-RegulationVariantViralViral Regulatory ProteinsVirus DiseasesVirus ReplicationXeroderma Pigmentosumactivating transcription factorc-myc Genescell transformationclastogenendonucleaseexperimental studygain of functiongain of function mutationgenome-wideinhibitorinsertion/deletion mutationnucleic acid structurepreventpromoterrepair enzymeresponsesenescencesynergismtranscription factortransmission processultraviolet irradiation
项目摘要
The human T-cell leukemia virus type 1 (HTLV-1) is a complex human delta retrovirus that infects 10-20 million people worldwide. Approximately 3-5% of infected individuals develop an intractable T cell malignancy known as adult T cell leukemia/lymphoma (ATL) decades later. How HTLV-1 infection progresses to ATL is not fully understood. Two viral regulatory proteins, Tax and HBZ, encoded by the sense and antisense viral mRNA transcripts, respectively, are crucial for causing ATL. Tax, the viral trans-activator/oncoprotein, is a robust activator of viral replication and IKK/NF-κB signaling, and a potent clastogen that induces DNA double-strand breaks (DSBs). It is thought to be the cause for the extensive genomic instability of ATL, which, on average, contains 59.5 structural variations in its genome. We recently discovered that NF-κB hyperactivation by Tax results in the co-transcriptional accumulation of a nucleic acid structure known as an R-loop. And R-loop excision by Xeroderma pigmentosum F (XPF) and XPG, two endonucleases of the transcription-coupled nucleotide excision repair (TC-NER) pathway, leads to DNA DSBs. This finding provides a mechanistic explanation for the genomic instability of ATL and the senescence-inducing activities of Tax. Indeed, NF-κB blockade prevents Tax- induced R-loop accumulation, DNA damage, and senescence. And the silencing of XPF and XPG mitigates Tax senescence, while deficiency in either or both frequently occurs in ATL cells of all types. Importantly, NF-κB is constitutively active in ATL, and ATL cells are resistant to Tax-senescence, suggesting that they have evolved adaptive changes to benefit from the survival and proliferation advantages conferred by Tax and NF-κB. Considering our discoveries outlined above and recent evidence showing that Tax is expressed intermittently in intense bursts in ATL cell lines and HTLV-1-infected T lymphocytes cultured ex vivo, we posit that most de novo HTLV-1 infections result in active viral replication, during which potent NF-κB activation by Tax drives the accumulation of R-loops that promote DNA DSBs, leading to senescence. In a fraction of infected T cells, HTLV- 1 proviruses likely integrate into transcriptionally quiescent chromosomal regions, establishing latent viral infection. During latency, HBZ, expressed from a distinct promoter in the 3’ LTR, dampens Tax activities to inhibit viral replication and, at the same time, stimulates the clonal expansion of the latently infected cells. We further posit that Tax, expressed intermittently during viral reactivation, targets R-loops and DNA DSBs to specific NF- kB-regulated genes, causing their inactivation and facilitating ATL development. Finally, we hypothesize that during ATL evolution, gain-of-function mutations and copy number variants of interferon regulatory factor 4 (IRF4) gene are selected to enable cellular adaptation to the DNA damage and senescence response induced by Tax and NF-κB. We will test these hypotheses in two specific aims: Aim 1 To determine how Tax/NF-κB - induced R-loops impact host cell genome and cell fate. Aim 2 To elucidate how ATL cells accommodate chronic NF-κB activation.
人类T细胞白血病病毒1型(HTLV-1)是一种复杂的人类δ逆转录病毒,感染全球1000万至2000万人。大约3-5%的受感染个体在数十年后发展为称为成人T细胞白血病/淋巴瘤(ATL)的难治性T细胞恶性肿瘤。HTLV-1感染如何进展为ATL尚不完全清楚。分别由正义和反义病毒mRNA转录物编码的两种病毒调节蛋白Tax和HBZ对于引起ATL至关重要。Tax是一种病毒反式激活因子/癌蛋白,是病毒复制和IKK/NF-κB信号传导的强激活因子,也是一种诱导DNA双链断裂(DSB)的强效断裂剂。它被认为是ATL广泛的基因组不稳定性的原因,ATL基因组中平均包含59.5个结构变异。我们最近发现Tax对NF-κB的过度激活导致了一种称为R环的核酸结构的共转录积累。着色性干皮病F(XPF)和XPG(转录偶联核苷酸切除修复(TC-NER)途径的两种核酸内切酶)的R环切除导致DNA双链断裂。这一发现为ATL的基因组不稳定性和Tax的衰老诱导活性提供了机制解释。事实上,NF-κB阻断防止Tax诱导的R环积累、DNA损伤和衰老。XPF和XPG的沉默减轻了Tax衰老,而在所有类型的ATL细胞中,任一种或两种都经常发生缺陷。重要的是,NF-κB在ATL中具有组成性活性,ATL细胞对Tax衰老具有抗性,表明它们已经进化出适应性变化,以受益于Tax和NF-κB赋予的存活和增殖优势。考虑到我们的上述发现和最近的证据表明,Tax在ATL细胞系和离体培养的HTLV-1感染的T淋巴细胞中间歇性地强烈爆发表达,我们认为大多数新生HTLV-1感染导致活跃的病毒复制,在此期间,Tax对NF-κB的有效激活驱动了促进DNA DSB的R环的积累,导致衰老。在一部分感染的T细胞中,HTLV- 1前病毒可能整合到转录静止的染色体区域,建立潜伏的病毒感染。在潜伏期期间,从3' LTR中的不同启动子表达的HBZ抑制Tax活性以抑制病毒复制,同时刺激潜伏感染细胞的克隆扩增。我们进一步证实,Tax在病毒再活化过程中间歇性表达,将R环和DNA DSB靶向特定的NF-κ B调节基因,导致其失活并促进ATL的发展。最后,我们假设在ATL进化过程中,干扰素调节因子4(IRF 4)基因的功能获得性突变和拷贝数变异体被选择,以使细胞适应Tax和NF-κB诱导的DNA损伤和衰老反应。我们将在两个具体目标中检验这些假设:目标1确定Tax/NF-κB诱导的R环如何影响宿主细胞基因组和细胞命运。目的2探讨ATL细胞对慢性NF-κB活化的调节作用。
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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CHOU-ZEN GIAM其他文献
CHOU-ZEN GIAM的其他文献
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{{ truncateString('CHOU-ZEN GIAM', 18)}}的其他基金
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8052727 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8607791 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8396677 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
7866744 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8448784 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8265753 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8607461 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8791965 - 财政年份:2010
- 资助金额:
$ 22.78万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
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8214695 - 财政年份:2010
- 资助金额:
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7389697 - 财政年份:2008
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