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

Author:

He Yunlong,Pasupala Nagesh,Zhi Huijun,Dorjbal Batsuhk,Hussain Imran,Shih Hsiu-Ming,Bhattacharyya SharmisthaORCID,Biswas Roopa,Miljkovic MilosORCID,Semmes Oliver JohnORCID,Waldmann Thomas A.ORCID,Snow Andrew L.ORCID,Giam Chou-ZenORCID

Abstract

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.

Funder

HHS | NIH | National Cancer Institute

DOD | Uniformed Services University of the Health Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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