NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (10), p.1-9
• Main Authors: He, Yunlong, Pasupala, Nagesh, Zhi, Huijun, Dorjbal, Batsuhk, Hussain, Imran, Shih, Hsiu-Ming, Bhattacharyya, Sharmistha, Biswas, Roopa, Miljkovic, Milos, Semmes, Oliver John, Waldmann, Thomas A., Snow, Andrew L., Giam, Chou-Zen
• Format: Article
• Language: English
• Subjects: Accumulation; Adult T cell leukemia; Biological Sciences; Cell activation; Cell culture; Cell proliferation; Damage accumulation; Deoxyribonucleic acid; DNA; DNA damage; Gene silencing; Irradiation; Leukemia; Lymphocytes; Lymphocytes T; NF-κB protein; Nucleotide excision repair; Nucleotides; R-loops; Repair; Ribonuclease H1; RNA-mediated interference; Senescence; Tax increases; Tax protein; Ultraviolet radiation; Xeroderma pigmentosum
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2005568118

Constitutive NF-κB activation (NF-κBCA) 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-κBCA 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-κBCA. How NF-κBCA induces senescence, and how ATL cells maintain NF-κBCA and avert senescence, remain unclear. Here we report that NF-κBCA 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-κBCA later. We suggest that TC-NER deficits and excess R-loop accumulation represent specific vulnerabilities that may be targeted for ATL treatment.