NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2021
- Source ID
- 10.1073/pnas.2005568118
Entities
People
- Andrew L. Snow
- Batsuhk Dorjbal
- Chou-Zen Giam
- Hsiu-ming Shih
- Huijun Zhi
- Imran Hussain
- Miloš D Miljković
- Nagesh Pasupala
- Oliver John Semmes
- Roopa Biswas
- Sharmistha Bhattacharyya
- Thomas Waldmann
- Yunlong He
Organizations
- Academia Sinica
- Eastern Virginia Medical School
- National Cancer Institute
- Uniformed Services University of the Health Sciences