{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:43:02Z","timestamp":1790797382714,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T00:00:00Z","timestamp":1650672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21CA216660"],"award-info":[{"award-number":["R21CA216660"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Uniformed Services University","award":["HU0001-14-1-0061"],"award-info":[{"award-number":["HU0001-14-1-0061"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia\/lymphoma (ATL) in 3\u20135% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK\/NF-\u03baB and a clastogen. While NF-\u03baB activities are associated with cell survival and proliferation, constitutive NF-\u03baB activation (NF-\u03baB hyperactivation) by Tax leads to senescence and oncogenesis. Until recently, the mechanisms underlying the DNA damage and senescence induced by Tax and NF-\u03baB were unknown. Current data indicate that NF-\u03baB 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-\u03baB 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-\u03baB, 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-\u03baB. In this review, the roles of R-loops in Tax- and NF-\u03baB-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.<\/jats:p>","DOI":"10.3390\/v14050877","type":"journal-article","created":{"date-parts":[[2022,4,24]],"date-time":"2022-04-24T02:22:02Z","timestamp":1650766922000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["NF-\u03baB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Chou-Zen","family":"Giam","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Rockville, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagesh","family":"Pasupala","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Rockville, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1200\/JCO.2008.18.2428","article-title":"Definition, prognostic factors, treatment, and response criteria of adult t-cell leukemia-lymphoma: A proposal from an international consensus meeting","volume":"27","author":"Tsukasaki","year":"2009","journal-title":"J. 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