Role of long non-coding RNAs and RNA-binding proteins in p53 signaling

Division Of Basic Sciences - Nci

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Abstract

Our research is focused on investigating the function and mechanism of novel lncRNAs and RNA-binding proteins (RBPs) in p53 signaling using colorectal cancer as a model. We hypothesize that in response to DNA damage, select p53-regulated lncRNAs and RBPs play a critical role in regulating a subset of the p53-regulated transcriptome to control cell survival and/or cell cycle arrest. As a first step towards achieving our goal, we have identified novel lncRNAs transactivated by p53 in multiple, p53-proficient colorectal cell lines. To examine their function, we use CRISPR/Cas9 to abolish their expression and for phenotypic studies. To determine their role in regulating the transcriptome, we employ gene expression profiling from candidate lncRNA-proficient and lncRNA-deficient isogenic cell lines in the presence or absence of DNA damage. In parallel, we perform lncRNA pulldowns to identify the factors bound by the candidate lncRNA. To examine the role of these lncRNAs in cancer pathogenesis we conduct experiments in colorectal cancer patient samples and in mice. These investigations will further our understanding of the function and mechanism of action of novel p53-regulated lncRNAs in the DNA damage response and their involvement in colorectal cancer. In addition to lncRNAs, we are also investigating the roles of RBPs in the p53 pathway. Our recent study on ZMAT3, a p53-induced RBP, has uncovered a function of ZMAT3 in regulating mRNA splicing. Currently, we are investigating how other p53-induced RBPs function in mediating the effects of p53.