Journal Article

Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3

Perez-Pinera, Pablo, Shabalina, Svetlana A, Yang, Yuan, Li, Xiao Ling, Woods, Wendy S, Dasso, Mary, Moriarity, Branden S, Jones, Matthew F, Frier, Susan M, Prasanth, Kannanganattu V, Lal, Ashish, Subramanian, Murugan, Wakefield, Lalage M, Gryder, Berkley, Mo, Min, Chaudhary, Ritu, Zhu, Yuelin, Jenkins, Lisa M

2017

Overview

Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a prosurvival function in human colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the enhancer region of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells. Though DNA contains the information needed to build the proteins that keep cells alive, only 2% of the DNA in a human cell codes for proteins. The remaining 98% is referred to as non-coding DNA. The information in some of these non-coding regions can still be copied into molecules of RNA, including long molecules called lncRNAs. Little is known about what lncRNAs actually do, but growing evidence suggests that these molecules are important for a number of vital processes including cell growth and survival. When the DNA in an animal cell gets damaged, the cell needs to decide whether to pause growth and repair the damage, or to kill itself if the harm is too great. One of the best-studied proteins guiding this decision is the p53 protein, which increases the number of protein-coding genes needed to carry out either option in this decision. That is to say that, p53 regulates the genes needed to kill the cell and the genes needed to temporarily pause its growth and repair the damage, which instead keeps the cell alive. So, how does the p53 protein guide the decision, and are lncRNA molecules involved? Using human colon cancer cells, Chaudhary et al. now report that when DNA is damaged, the levels of a specific lncRNA increase 100-fold. Further experiments showed that this lncRNA – named PINCR, which refers to p53-induced noncoding RNA – promotes the survival of cells. Chaudhary et al. showed that PINCR molecules do this by recruiting a protein called Matrin 3 to a certain region in the DNA called an enhancer and then links it to promoter region in the DNA of specific genes that temporarily pause cell growth but keep the cell alive. This in turn activates these ‘pro-survival genes’. In further experiments, when the PINCR molecules were essentially deleted, p53 was not able to fully activate these genes and as a result more of the cells died. Together these findings increase our knowledge of how lncRNAs can work, especially in the context of DNA damage in cancer cells. A next important step will be to uncover other roles for the PINCR molecule in both cancer and healthy cells.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Apoptosis / Binding sites (Biochemistry) / Biology / BTG2 protein / Cancer Biology / Cancer cells / Cell cycle / Cell Line, Tumor / Cell Proliferation / Clonal deletion / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - pathology / Deoxyribonucleic acid / DNA / DNA Damage / Gene deletion / Gene Expression Regulation / Genes / Genetic aspects / Genetics / Health aspects / Humans / Hypersensitivity / Laboratories / lncRNA / Matrin 3 / Medical research / Metabolism / Methods / Nuclear Matrix-Associated Proteins - metabolism / p53 / p53 Protein / PINCR / Proteins / Ribonucleic acid / RNA / RNA sequencing / RNA, Long Noncoding - metabolism / RNA-binding protein / RNA-Binding Proteins - metabolism / RP3-326I13.1 / Software / Tumor Suppressor Protein p53 - metabolism