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Published on: April 10, 2018
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GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability
Wang Lai Hu1,2,3, Lei Jin4, An Xu1
1Chinese 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.
Nature Cell Biology
|March 30, 2018
Summary
The long non-coding RNA GUARDIN maintains DNA structure by regulating TRF2 and BRCA1. GUARDIN deficiency leads to genomic instability and inhibits cancer growth, suggesting it as a potential cancer treatment target.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cellular processes.
- The specific functions of lncRNAs in maintaining DNA structure and genomic integrity are not fully understood.
- The p53 pathway is crucial for DNA damage response, but the involvement of lncRNAs in this process requires further investigation.
Purpose of the Study:
- To investigate the role of the p53-responsive lncRNA GUARDIN in maintaining genomic integrity.
- To elucidate the molecular mechanisms by which GUARDIN preserves DNA structure under normal and stress conditions.
- To evaluate the therapeutic potential of targeting GUARDIN in cancer treatment.
Main Methods:
- Assessing the impact of GUARDIN on genomic integrity under steady-state and genotoxic stress conditions.
- Investigating GUARDIN's interaction with microRNA-23a to regulate telomeric repeat-binding factor 2 (TRF2) expression.
- Analyzing GUARDIN's role as an RNA scaffold in the heterodimerization of breast cancer 1 (BRCA1) and BRCA1-associated RING domain protein 1 (BARD1).
- Evaluating the effects of GUARDIN silencing on apoptosis, senescence, cytotoxicity, and cancer xenograft growth.
Main Results:
- GUARDIN is essential for maintaining genomic integrity under both steady-state and genotoxic stress.
- GUARDIN prevents chromosome end-to-end fusion by sequestering microRNA-23a, thereby maintaining TRF2 expression.
- GUARDIN stabilizes BRCA1 by facilitating BRCA1-BARD1 heterodimerization.
- GUARDIN silencing induces apoptosis and senescence, enhances sensitivity to genotoxic stress, and inhibits tumor growth in vivo.
Conclusions:
- The p53-responsive lncRNA GUARDIN plays a critical role in maintaining genomic stability.
- GUARDIN functions by regulating key proteins involved in DNA repair and telomere maintenance, including TRF2 and BRCA1.
- GUARDIN represents a promising therapeutic target for cancer treatment due to its role in tumor suppression.
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