气候变化领域集成服务门户(CCPortal): NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia

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DOI	10.1073/pnas.2005568118
	NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia
	He Y.; Pasupala N.; Zhi H.; Dorjbal B.; Hussain I.; Shih H.-M.; Bhattacharyya S.; Biswas R.; Miljkovic M.; Semmes O.J.; Waldmann T.A.; Snow A.L.; Giam C.-Z.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Adult T cell leukemia; DNA damage; NF-κB activation; R-loop; Transcription-coupled nucleotide excision repair
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180358
作者单位	Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States; Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States; Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, 350, Taiwan; Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States; Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, United States; The Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, United States
推荐引用方式 GB/T 7714	He Y.,Pasupala N.,Zhi H.,等. NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia[J],2021,118(10).
APA	He Y..,Pasupala N..,Zhi H..,Dorjbal B..,Hussain I..,...&Giam C.-Z..(2021).NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	He Y.,et al."NF-κB–induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).