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

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2005568118. 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.

Keywords: DNA damage; NF-κB activation; R-loop; adult T cell leukemia; transcription-coupled nucleotide excision repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • DNA Damage*
  • DNA Repair*
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism*
  • Gene Products, tax / genetics
  • Gene Products, tax / metabolism*
  • HeLa Cells
  • Human T-lymphotropic virus 1 / genetics
  • Human T-lymphotropic virus 1 / metabolism*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / genetics
  • Leukemia-Lymphoma, Adult T-Cell / metabolism*
  • Leukemia-Lymphoma, Adult T-Cell / virology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*


  • DNA, Neoplasm
  • Gene Products, tax
  • NF-kappa B
  • Neoplasm Proteins
  • tax protein, Human T-lymphotrophic virus 1