NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia
Yunlong He, Nagesh Pasupala, Huijun Zhi, Batsuhk Dorjbal, Imran Hussain, Hsiu‐Ming Shih, Sharmistha Bhattacharyya, Roopa Biswas, Miloš D. Miljković, O. John Semmes, Thomas A. Waldmann, Andrew L. Snow, Chou‐Zen Giam
Abstract
Significance Cellular NF-κB activity is stringently regulated. Constitutive NF-κB activation (NF-κB CA ), however, frequently occurs in T/B cell malignancies including adult T cell leukemia (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We demonstrate that NF-κB CA via the HTLV-1 trans-activator/oncoprotein Tax causes R-loop accumulation, DNA double-strand breaks, and senescence and that R-loop processing by the transcription-coupled nucleotide excision repair (TC-NER) pathway contributes to senescence induction. We show that TC-NER deficits occur in ATL. They enable senescence escape and outgrowth of HTLV-1–infected and ATL cells with NF-κB CA , but render ATL cells hypersensitive to ultraviolet light. With NF-κB CA , ATL cells continue to accumulate abundant R-loops. TC-NER deficiency and excess R-loop accumulation represent vulnerabilities of ATL that can be exploited therapeutically.