Chaudhary Ritu, Gryder Berkley, Woods Wendy S, Subramanian Murugan, Jones Matthew F, Li Xiao Ling, Jenkins Lisa M, Shabalina Svetlana A, Mo Min, Dasso Mary, Yang Yuan, Wakefield Lalage M, Zhu Yuelin, Frier Susan M, Moriarity Branden S, Prasanth Kannanganattu V, Perez-Pinera Pablo, Lal Ashish
Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.
Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.
Elife. 2017 Jun 5;6:e23244. doi: 10.7554/eLife.23244.
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 (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a prosurvival function in human colorectal cancer cells (CRC) and tumor growth . Targeted deletion of in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including and . Using a novel RNA pulldown approach that utilized endogenous S1-tagged , we show that 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//Matrin 3 axis in response to DNA damage in CRC cells.
人们已经发现了数以千计的长链非编码RNA(lncRNA),然而绝大多数lncRNA的功能仍不清楚。在此,我们表明一种由p53调控的lncRNA(我们将其命名为p53诱导非编码RNA),在DNA损伤后被诱导约100倍,并在人结肠癌细胞(CRC)中发挥促生存功能以及促进肿瘤生长。在结肠癌细胞中靶向缺失该lncRNA会显著损害G1期阻滞,并诱导细胞对化疗药物的超敏反应。该lncRNA调节了参与G1期阻滞和凋亡的一部分p53靶标的诱导,包括[具体基因1]和[具体基因2]。使用一种利用内源性S1标记该lncRNA的新型RNA下拉方法,我们表明该lncRNA通过与RNA结合蛋白Matrin 3结合而与这些基因的增强子区域相关联,而Matrin 3又与p53相关联。我们的研究结果揭示了p53/该lncRNA/Matrin 3轴在结肠癌细胞对DNA损伤反应中的关键促生存功能。