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Nat Cell Biol. 2018 Apr;20(4):492-502. doi: 10.1038/s41556-018-0066-7. Epub 2018 Mar 28.

GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability.

Hu WL1,2,3, Jin L4, Xu A1, Wang YF5, Thorne RF2,6, Zhang XD7,8, Wu M9,10.

Author information

1
Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, CAS Centre for Excellence in Cell and Molecular Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, University of Science and Technology of China, Hefei, China.
2
Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou, China.
3
Department of Immunology, Anhui Medical University, Hefei, China.
4
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
5
Department of Pathophysiology, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
6
School of Environmental and Life Sciences, University of Newcastle, Newcastle, New South Wales, Australia.
7
Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou, China. Xu.Zhang@newcastle.edu.au.
8
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia. Xu.Zhang@newcastle.edu.au.
9
Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, CAS Centre for Excellence in Cell and Molecular Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, University of Science and Technology of China, Hefei, China. wumian@ustc.edu.cn.
10
Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou, China. wumian@ustc.edu.cn.

Abstract

The list of long non-coding RNAs (lncRNAs) involved in the p53 pathway of the DNA damage response is rapidly expanding, but whether lncRNAs have a role in maintaining the de novo structure of DNA is unknown. Here, we demonstrate that the p53-responsive lncRNA GUARDIN is important for maintaining genomic integrity under steady-state conditions and after exposure to exogenous genotoxic stress. GUARDIN is necessary for preventing chromosome end-to-end fusion through maintaining the expression of telomeric repeat-binding factor 2 (TRF2) by sequestering microRNA-23a. Moreover, GUARDIN also sustains breast cancer 1 (BRCA1) stability by acting as an RNA scaffold to facilitate the heterodimerization of BRCA1 and BRCA1-associated RING domain protein 1 (BARD1). As such, GUARDIN silencing triggered apoptosis and senescence, enhanced cytotoxicity of additional genotoxic stress and inhibited cancer xenograft growth. Thus, GUARDIN may constitute a target for cancer treatment.

PMID:
29593331
DOI:
10.1038/s41556-018-0066-7

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