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NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells

Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3–5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities are associated with cel...

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Autores principales: Giam, Chou-Zen, Pasupala, Nagesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147355/
https://www.ncbi.nlm.nih.gov/pubmed/35632619
http://dx.doi.org/10.3390/v14050877
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author Giam, Chou-Zen
Pasupala, Nagesh
author_facet Giam, Chou-Zen
Pasupala, Nagesh
author_sort Giam, Chou-Zen
collection PubMed
description Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3–5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities are associated with cell survival and proliferation, constitutive NF-κB activation (NF-κB hyperactivation) by Tax leads to senescence and oncogenesis. Until recently, the mechanisms underlying the DNA damage and senescence induced by Tax and NF-κB were unknown. Current data indicate that NF-κB hyperactivation by Tax causes the accumulation of a nucleic acid structure known as an R-loop. R-loop excision by the transcription-coupled nucleotide excision repair (TC-NER) endonucleases, Xeroderma pigmentosum F (XPF), and XPG, in turn, promotes DNA double-strand breaks (DSBs). NF-κB blockade prevents Tax-induced R-loop accumulation, DNA damage, and senescence. In the same vein, the silencing of XPF and XPG mitigates Tax senescence, while deficiency in either or both frequently occurs in ATL of all types. ATL cells maintain constitutively active NF-κB, accumulate R-loops, and resist Tax-induced senescence. These results suggest that ATL cells must have acquired adaptive changes to prevent senescence and benefit from the survival and proliferation advantages conferred by Tax and NF-κB. In this review, the roles of R-loops in Tax- and NF-κB-induced DNA DSBs, senescence, and ATL development, and the epigenetic and genetic alterations that arise in ATL to reduce R-loop-associated DNA damage and avert senescence will be discussed.
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spelling pubmed-91473552022-05-29 NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells Giam, Chou-Zen Pasupala, Nagesh Viruses Review Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3–5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities are associated with cell survival and proliferation, constitutive NF-κB activation (NF-κB hyperactivation) by Tax leads to senescence and oncogenesis. Until recently, the mechanisms underlying the DNA damage and senescence induced by Tax and NF-κB were unknown. Current data indicate that NF-κB hyperactivation by Tax causes the accumulation of a nucleic acid structure known as an R-loop. R-loop excision by the transcription-coupled nucleotide excision repair (TC-NER) endonucleases, Xeroderma pigmentosum F (XPF), and XPG, in turn, promotes DNA double-strand breaks (DSBs). NF-κB blockade prevents Tax-induced R-loop accumulation, DNA damage, and senescence. In the same vein, the silencing of XPF and XPG mitigates Tax senescence, while deficiency in either or both frequently occurs in ATL of all types. ATL cells maintain constitutively active NF-κB, accumulate R-loops, and resist Tax-induced senescence. These results suggest that ATL cells must have acquired adaptive changes to prevent senescence and benefit from the survival and proliferation advantages conferred by Tax and NF-κB. In this review, the roles of R-loops in Tax- and NF-κB-induced DNA DSBs, senescence, and ATL development, and the epigenetic and genetic alterations that arise in ATL to reduce R-loop-associated DNA damage and avert senescence will be discussed. MDPI 2022-04-23 /pmc/articles/PMC9147355/ /pubmed/35632619 http://dx.doi.org/10.3390/v14050877 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Giam, Chou-Zen
Pasupala, Nagesh
NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
title NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
title_full NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
title_fullStr NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
title_full_unstemmed NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
title_short NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
title_sort nf-κb-induced r-loops and genomic instability in htlv-1-infected and adult t-cell leukemia cells
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147355/
https://www.ncbi.nlm.nih.gov/pubmed/35632619
http://dx.doi.org/10.3390/v14050877
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