國家衛生研究院 NHRI:Item 3990099045/13239
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    题名: NF-kappaB-induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia
    其它题名: NF-κB-induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia
    作者: 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
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: 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.
    日期: 2021-03-09
    關聯: 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
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