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Positive and Negative Feedback Loops in the P53 and Mrna 3′ Processing Pathways

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Positive and Negative Feedback Loops in the P53 and Mrna 3′ Processing Pathways Positive and negative feedback loops in the p53 and mRNA 3′ processing pathways Emral Devanya,1, Xiaokan Zhanga,1, Ji Yeon Parkb, Bin Tianb, and Frida Esther Kleimana,2 aChemistry Department, Hunter College and Graduate Center, City University of New York, New York, NY 10065; and bDepartment of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07101 Edited by Carol Prives, Columbia University, New York, NY, and approved January 17, 2013 (received for review July 20, 2012) Although the p53 network has been intensively studied, genetic signal AREs in their 3′ untranslated regions (UTRs), which have analyses long hinted at the existence of components that remained been shown to play significant roles in mRNA stability regulation elusive. Recent studies have shown regulation of p53 at the mRNA (12). PARN has been shown to be involved in ARE-mediated level mediated via both the 5′ and the 3′ untranslated regions and deadenylation and to promote tristetraprolin (TTP)-directed affecting the stability and translation efficiency of the p53 mRNA. deadenylation in vitro (13). KH-type splicing regulatory protein Here, we provide evidence of a feedback loop between p53 and the recruits PARN to ARE-containing mRNAs to initiate the poly(A) tail shortening that is followed by exosome-mediated degradation poly(A)-specific ribonuclease (PARN), in which PARN deadenylase (14). Interestingly, tumor suppressors, such as breast cancer type keeps p53 levels low in nonstress conditions by destabilizing p53 1 susceptibility protein (BRCA1) and BRCA1-associated RING mRNA, and the UV-induced increase in p53 activates PARN dead- domain protein (BARD1), associated to the polyadenylation enylase, regulating gene expression during DNA damage response factor CstF1 have been shown to regulate deadenylation by in a transactivation-independent manner. This model is innovative functional interactions with PARN deadenylase (5). because it provides insights into p53 function and the mechanisms Extending those studies, here we are investigating the possi- behind the regulation of mRNA 3′ end processing in different cel- bility that p53 might regulate not only mRNA 3′ cleavage (4) but lular conditions. also PARN-dependent deadenylation in different cellular con- ditions. As part of these studies, we also identified the mRNA deadenylation | mRNA 3′ processing | mRNA steady state levels | targets of PARN in nonstress conditions. Our results provide gene expression control evidence of a unique feedback loop between p53 and PARN, in which PARN deadenylase keeps p53 levels low in nonstress conditions by destabilizing p53 mRNA through its 3′ UTR, and ownstream signaling in the p53 pathway includes several cel- the UV-induced increase in p53 activates PARN, representing Dlular responses. The expression of a large number of genes a mechanism of gene expression regulation in a transactivation- involved in DNA repair, cell cycle arrest, and/or apoptosis is reg- independent manner. ulated by transactivating properties of p53. This occurs via specific DNA binding of the p53 protein to a p53 response element that is Results found either in promoters or introns of target genes (1). Trans- activation-independent functions of p53 have also been described To investigate the role of p53 in deadenylation, we used a group of BIOCHEMISTRY isogenic cell lines that express different levels of p53 (Fig. 1A and (2). For example, certain microRNAs (miRNAs) are regulated by Fig. S1): the colon cancer HCT116 and p53-null HCT116 cell lines, p53, and these miRNAs cause dramatic changes in gene expres- the colon carcinoma RKO and RKO-E6 (low p53 levels) cell lines, sion, offering an indirect p53-mediated control of gene expression and the mouse embryonic fibroblasts (MEFs) and p53-null MEFs. at the posttranscriptional level (3). Recently, we showed that p53 Nuclear extracts (NEs) from those cells were assayed for dead- can inhibit mRNA 3′ cleavage through its interaction with the enylation activity using a radiolabeled L3(A ) RNA substrate as cleavage stimulation factor 1 (CstF1) (4). CstF1 can also interact 30 fi described (5). As described in previous studies (5), Fig. 1A shows with poly(A)-speci c ribonuclease (PARN) deadenylase, and the that deadenylation activity in NEs of RKO cells treated with con- CstF1/PARN complex formation has a role in the regulation of fi ′ trol siRNA increased signi cantly after UV treatment. Interestingly, gene expression by inhibition of mRNA 3 cleavage and activation siRNA-mediated knockdown of p53 in RKO cells abolished the of deadenylation upon DNA damage (5). PARN, an mRNA decay UV-induced activation of deadenylation, suggesting that p53 enzyme, has been studied extensively in vitro at the biochemical levels might activate deadenylation. Consistent with this, RKO- levels but very little is known of its biological targets and its role in E6, p53-null HCT116, and p53-null MEFs cells did not show UV- different cellular conditions. Recently, it has been shown that induced activation of deadenylation, which was observed in RKO, PARN regulates the expression of genes involved in mRNA me- HCT116, and MEFs cells. Importantly, only increasing amounts tabolism, transcription, and cell motility in mouse myoblasts (6). of either full-length His-p53 (Fig. 1 B and C) or the C-terminal Our studies indicate that the CstF/PARN complex can decrease fragment of p53 (Fig. 1C) can induce deadenylation in a reaction the mRNA levels of housekeeping genes under DNA-damaging using a limited amount of His-PARN in a cell-free assay, sug- conditions and of genes involved in cell growth and differentiation gesting that this is a transactivation-independent function of under nonstress conditions (5). p53. However, neither the two p53 derivatives that lacked the Almost all eukaryotic mRNA precursors, with the exception of C-terminal region of p53 nor GST alone had an effect on the histones, undergo a cotranscriptional cleavage followed by poly- ′ fi deadenylation reaction (Fig. 1C). None of the His-p53 derivatives adenylation at the 3 end. This rst round of polyadenylation is were able to deadenylate the substrate in the absence of His- considered a default modification for most mRNAs and confers stability. In contrast, activation of deadenylation alters the length of poly(A) tails, affecting mRNA stability, transport, or trans- lation initiation, and hence gene expression (7). Thus, mecha- Author contributions: E.D., X.Z., B.T., and F.E.K. designed research; E.D., X.Z., and J.Y.P. performed research; E.D., X.Z., and J.Y.P. contributed new reagents/analytic tools; E.D., nisms controlling deadenylation are highly regulated and play key X.Z., J.Y.P., B.T., and F.E.K. analyzed data; and E.D., X.Z., B.T., and F.E.K. wrote the paper. roles in cellular responses, such as mRNA surveillance, DNA fl damage response (DDR), and tumor progression, as well as cell The authors declare no con ict of interest. development and differentiation (5, 8–11). Deadenylation of This article is a PNAS Direct Submission. mRNA is regulated by miRNAs, adenylate-uridylate–rich element 1E.D. and X.Z. contributed equally to this work. (ARE) binding proteins, polyadenylation factors, and RNA bind- 2To whom correspondence should be addressed. E-mail: [email protected]. ing (RB) factors that recognize cis-acting sequences in the target. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. About 12% of mammalian mRNAs bear important regulatory 1073/pnas.1212533110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1212533110 PNAS | February 26, 2013 | vol. 110 | no. 9 | 3351–3356 Downloaded by guest on September 26, 2021 A RKO RKO-E6 siRNA: control p53 --- HCT116 HCT116 p53 -/- MEF MEF p53 -/- UV: - + - + - + - UV: - + - + UV: - + - + -L3(A30) -L3(A ) 30 -L3(A30) -L3 -L3 -L3 RD: 34 58 28 27 21 22 RD: 14 42 0.2 0.2 RD: 18 37 16 14 B C His-p53: - - --- His-p53: - - - 0.1 0.25 0.5 0.5 ng PARN: 1 0.2 0.2 0.2 0.2 0.2 - - - - 0.2 0.2 0.2 ng PARN: 1 0.5 0.2 0.2 0.2 0.2 - ng GST: - - - - - - - - - - 0.1 0.25 0.5 ng -L3(A30) -L3(A30) -L3 -L3 RD: 12 9 4 32 57 76 0 RD: 26 14 52 12 35 9 3.5 2 2 2 2 2 2.5 Fig. 1. The levels of deadenylation correlate with expression levels of p53. (A) Samples from cells expressing different levels of p53 show different levels of deadenylation. A representative deadenylation reaction from three independent assays is shown. siRNA-mediated knockdown of p53 abolishes UV-induced ac- tivation of deadenylation in RKO cells. NEs of the indicated cells treated with UV irradiation and allowed to recover for 2 h were analyzed for radiolabeled L3(A30) deadenylation as described (4, 5). NEs from RKO cells treated with p53/control siRNA and UV irradiation were also analyzed. Positions of the polyadenylated RNA L3(A30) and the L3 deadenylated product are indicated. Numbers beneath gel lanes indicate relative deadenylation (RD). RD was calculated as [L3 fragment/ (L3 fragment + L3 (A30)] × 100. Quantifications were done with ImageJ software (http://rsb.info.nih.gov/ij/). (B) p53 can activate PARN-dependent dead- enylation in vitro. Deadenylation assays using different concentrations of His-PARN were performed in the presence of capped L3(A30)RNAsubstrateasde- scribed (5) and increasing amounts of His-p53. Reactions were analyzed as in A. (C) The C-terminal domain of p53 activates PARN in vitro. Deadenylation assays were performed as in B with the addition of either full-length p53 (FL) or His-p53 derivatives. The truncated forms of p53 used in this assay were described before (4) and include p53 amino acids 1–293, p53 amino acids 94–293 (DNA binding domain), and p53 amino acids 94–393.
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