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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
A549 Cells
-
Animals
-
Antineoplastic Agents / pharmacology
-
Apoptosis
-
BRCA1 Protein / genetics
-
BRCA1 Protein / metabolism
-
Cell Proliferation
-
Cellular Senescence
-
Gene Expression Regulation, Neoplastic
-
Gene Silencing
-
Genomic Instability* / drug effects
-
HCT116 Cells
-
HEK293 Cells
-
Humans
-
Male
-
Mice, Inbred BALB C
-
Mice, Nude
-
MicroRNAs / genetics
-
MicroRNAs / metabolism
-
Neoplasms / drug therapy
-
Neoplasms / genetics*
-
Neoplasms / metabolism
-
Neoplasms / pathology
-
Nucleic Acid Conformation
-
RNA, Long Noncoding / genetics*
-
RNA, Long Noncoding / metabolism
-
Signal Transduction
-
Telomeric Repeat Binding Protein 2 / genetics
-
Telomeric Repeat Binding Protein 2 / metabolism
-
Tumor Burden
-
Tumor Suppressor Protein p53 / genetics*
-
Tumor Suppressor Protein p53 / metabolism
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism
Substances
-
Antineoplastic Agents
-
BRCA1 Protein
-
BRCA1 protein, human
-
MIRN23a microRNA, human
-
MicroRNAs
-
RNA, Long Noncoding
-
TERF2 protein, human
-
TP53 protein, human
-
Telomeric Repeat Binding Protein 2
-
Tumor Suppressor Protein p53
-
Tumor Suppressor Proteins
-
BARD1 protein, human
-
Ubiquitin-Protein Ligases