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：
CHOU-ZEN GIAM
金额：
$ 22.78万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
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：
https://reporter.nih.gov/project-details/10572907
关键词：
Ablation Acute Address Adult T-Cell Leukemia/Lymphoma B lymphoid malignancy Biological CD4 Positive T Lymphocytes CRISPR/Cas technology Cell Cycle Cell Cycle Arrest Cell Line Cell Proliferation Cells Characteristics Chronic Clonal Expansion Complex Copy Number Polymorphism DNA Damage DNA Double Strand Break DNA Sequence DNA cassette Data Development Evolution Excision Feedback G1/S Transition Gene Combinations Genes Genetic Transcription Genome Genomic Instability Genomics Human Human Genome Human T-lymphotropic virus 1 Hypersensitivity IRF4 gene Immune response Individual Infection Latent virus infection phase Leucine Zippers Light Lymphoma cell Malignant Neoplasms Maps Measures Mediating Messenger RNA Mitotic Molecular Mutation NF-kappa B Oncoproteins Pathogenesis Pathway interactions Persons Process Productivity Proliferating Proviruses Recurrence Regulation Resistance Retroviridae Signal Transduction Survivors T-Cell Development T-Lymphocyte Taxes Techniques Testing Therapeutic Time Trans-Activators Transcript Transcription Factor AP-1 Transcription-Coupled Repair Tumor Suppressor Proteins Up-Regulation Variant Viral Viral Regulatory Proteins Virus Diseases Virus Replication Xeroderma Pigmentosum activating transcription factor c-myc Genes cell transformation clastogen endonuclease experimental study gain of function gain of function mutation genome-wide inhibitor insertion/deletion mutation nucleic acid structure prevent promoter repair enzyme response senescence synergism transcription factor transmission process ultraviolet 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COMPREX人类三角病毒，感染10-20个感染个体的10-20个棘手的T细胞恶性肿瘤，称为成人T细胞白血病/淋巴瘤（ATL）HTLV-1感染如何ATL的进展不是完全的。有效的Clastogen DNA链链破裂（DSB）。核酸结构的tran脚本积累，称为R-L环和R-loop Concision。 ATL基因组不稳定性的机理解释和税收的衰老活性，NF-κB封锁征税诱导的R环，DNA损害，DNA损害以及XPF和XPG的税收减轻税收自由地发生在所有类型的ATL细胞中上面概述了上面的概述，最近的证据表明税收是ATL LINS和HTLV-1感染的tlymphocytes培养的体内的强烈爆发，这些体内大多数从头htlv-1感染都会导致主动病毒复制，在此期间，税收驱动力的有效的NF-κB激活了税收驱动力的积累。促进DSB的R环，导致衰老，在感染的T细胞中，HTLV-1速率在转录静止的染色体区域中，建立了潜在的病毒感染。我们感染了感染的细胞。选择IRF4基因以使细胞适应DNA损伤和室内室内的ERMINE税/NF-κB诱导的R环如何影响宿主细胞基因组和细胞命运，以阐明ATL如何适应慢性NF-κB活化。