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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/13239
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| Title: | NF-kappaB-induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia |
| Other Titles: | NF-κB-induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia |
| Authors: | He, Y;Pasupala, N;Zhi, H;Dorjbal, B;Hussain, I;Shih, HM;Bhattacharyya, S;Biswas, R;Miljkovic, M;Semmes, OJ;Waldmann, TA;Snow, AL;Giam, CZ |
| Contributors: | Institute of Molecular and Genomic Medicine |
| Abstract: | Constitutive NF-κB activation (NF-κB(CA)) confers survival and proliferation advantages to cancer cells and frequently occurs in T/B cell malignancies including adult T cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1). Counterintuitively, NF-κB(CA) by the HTLV-1 transactivator/oncoprotein Tax induces a senescence response, and HTLV-1 infections in culture mostly result in senescence or cell-cycle arrest due to NF-κB(CA) How NF-κB(CA) induces senescence, and how ATL cells maintain NF-κB(CA) and avert senescence, remain unclear. Here we report that NF-κB(CA) by Tax increases R-loop accumulation and DNA double-strand breaks, leading to senescence. R-loop reduction via RNase H1 overexpression, and short hairpin RNA silencing of two transcription-coupled nucleotide excision repair (TC-NER) endonucleases that are critical for R-loop excision-Xeroderma pigmentosum F (XPF) and XPG-attenuate Tax senescence, enabling HTLV-1-infected cells to proliferate. Our data indicate that ATL cells are often deficient in XPF, XPG, or both and are hypersensitive to ultraviolet irradiation. This TC-NER deficiency is found in all ATL types. Finally, ATL cells accumulate R-loops in abundance. Thus, TC-NER deficits are positively selected during HTLV-1 infection because they facilitate the outgrowth of infected cells initially and aid the proliferation of ATL cells with NF-κB(CA) later. We suggest that TC-NER deficits and excess R-loop accumulation represent specific vulnerabilities that may be targeted for ATL treatment. |
| Date: | 2021-03-09 |
| Relation: | Proceedings of the National Academy of Sciences of the United States of America. 2021 Mar 9;118(10):Article number e2005568118. |
| Link to: | http://dx.doi.org/10.1073/pnas.2005568118 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0027-8424&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000627429100006 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85102329927 |
| Appears in Collections: | [施修明] 期刊論文
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| PUB33649200.pdf | | 1622Kb | Adobe PDF | 271 | View/Open |
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