A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.

Department of Medical Biosciences Umeå University 90185 Umeå Sweden

ICCVS University of Gdańsk Science ul Wita Stwosza 63 80 308 Gdańsk Poland

Inserm U1162 27 rue Juliette Dodu 75010 Paris France

Laboratorio de Interacciones Biomoleculares y cáncer Instituto de Física Universidad Autónoma de San Luis Potosí Manuel Nava 6 Zona universitaria 78290 SLP México

RECAMO Masaryk Memorial Cancer Institute Zluty kopec 7 656 53 Brno Czech Republic

Zobrazit více v PubMed

Gomez-Lazaro M., Fernandez-Gomez F.J., Jordan J.. p53: twenty five years understanding the mechanism of genome protection. J. Physiol. Biochem. 2004; 60:287–307. PubMed

Toufektchan E., Toledo F.. The guardian of the genome revisited: p53 downregulates genes required for telomere maintenance, DNA repair, and centromere structure. Cancers (Basel). 2018; 10:E135. PubMed PMC

Brown C.J., Lain S., Verma C.S., Fersht A.R., Lane D.P.. Awakening guardian angels: drugging the p53 pathway. Nat. Rev. Cancer. 2009; 9:862–873. PubMed

Olivares-Illana V., Fahraeus R.. p53 isoforms gain functions. Oncogene. 2010; 29:5113–5119. PubMed

Dai C., Gu W.. p53 post-translational modification: deregulated in tumorigenesis. Trends Mol. Med. 2010; 16:528–536. PubMed PMC

Bode A.M., Dong Z.. Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer. 2004; 4:793–805. PubMed

Vieler M., Sanyal S.. p53 Isoforms and their implications in cancer. Cancers (Basel). 2018; 10:E288. PubMed PMC

Kastan M.B., Onyekwere O., Sidransky D., Vogelstein B., Craig R.W.. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991; 51:6304–6311. PubMed

Fu L., Benchimol S.. Participation of the human p53 3′UTR in translational repression and activation following gamma-irradiation. EMBO J. 1997; 16:4117–4125. PubMed PMC

Sajjanar B., Deb R., Raina S.K., Pawar S., Brahmane M.P., Nirmale A.V., Kurade N.P., Manjunathareddy G.B., Bal S.K., Singh N.P.. Untranslated regions (UTRs) orchestrate translation reprogramming in cellular stress responses. J. Therm. Biol. 2017; 65:69–75. PubMed

Kiss D.L., Oman K.M., Dougherty J.A., Mukherjee C., Bundschuh R., Schoenberg D.R.. Cap homeostasis is independent of poly(A) tail length. Nucleic Acids Res. 2016; 44:304–314. PubMed PMC

Pechmann S., Chartron J.W., Frydman J.. Local slowdown of translation by nonoptimal codons promotes nascent-chain recognition by SRP in vivo. Nat. Struct. Mol. Biol. 2014; 21:1100–1105. PubMed PMC

Aguirre B., Costas M., Cabrera N., Mendoza-Hernandez G., Helseth D.L. Jr, Fernandez P., de Gomez-Puyou M.T., Perez-Montfort R., Torres-Larios A., Gomez Puyou A.. A ribosomal misincorporation of Lys for Arg in human triosephosphate isomerase expressed in Escherichia coli gives rise to two protein populations. PLoS One. 2011; 6:e21035. PubMed PMC

Zhang G., Hubalewska M., Ignatova Z.. Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nat. Struct. Mol. Biol. 2009; 16:274–280. PubMed

Mayr C. Regulation by 3′-Untranslated regions. Annu. Rev. Genet. 2017; 51:171–194. PubMed

Shi Y., Di Giammartino D.C., Taylor D., Sarkeshik A., Rice W.J., Yates J.R. 3rd, Frank J., Manley J.L.. Molecular architecture of the human pre-mRNA 3′ processing complex. Mol. Cell. 2009; 33:365–376. PubMed PMC

Villalba A., Coll O., Gebauer F.. Cytoplasmic polyadenylation and translational control. Curr. Opin. Genet. Dev. 2011; 21:452–457. PubMed

Chen C.Y., Shyu A.B.. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem. Sci. 1995; 20:465–470. PubMed

Nabors L.B., Suswam E., Huang Y., Yang X., Johnson M.J., King P.H.. Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR. Cancer Res. 2003; 63:4181–4187. PubMed

Matoulkova E., Michalova E., Vojtesek B., Hrstka R.. The role of the 3′ untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA Biol. 2012; 9:563–576. PubMed

Fu L., Minden M.D., Benchimol S.. Translational regulation of human p53 gene expression. EMBO J. 1996; 15:4392–4401. PubMed PMC

Fu L., Ma W., Benchimol S.. A translation repressor element resides in the 3′ untranslated region of human p53 mRNA. Oncogene. 1999; 18:6419–6424. PubMed

Mazan-Mamczarz K., Galban S., Lopez de Silanes I., Martindale J.L., Atasoy U., Keene J.D., Gorospe M.. RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc. Natl. Acad. Sci. U.S.A. 2003; 100:8354–8359. PubMed PMC

Li F., Hu D.Y., Liu S., Mahavadi S., Yen W., Murthy K.S., Khalili K., Hu W.. RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells. Am. J. Physiol. Cell Physiol. 2010; 299:C1418–C1429. PubMed PMC

Licata L.A., Hostetter C.L., Crismale J., Sheth A., Keen J.C.. The RNA-binding protein HuR regulates GATA3 mRNA stability in human breast cancer cell lines. Breast Cancer Res. Treat. 2010; 122:55–63. PubMed

Nabors L.B., Gillespie G.Y., Harkins L., King P.H.. HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res. 2001; 61:2154–2161. PubMed

Galban S., Martindale J.L., Mazan-Mamczarz K., Lopez de Silanes I., Fan J., Wang W., Decker J., Gorospe M.. Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells. Mol. Cell Biol. 2003; 23:7083–7095. PubMed PMC

Tong X., Pelling J.C.. Enhancement of p53 expression in keratinocytes by the bioflavonoid apigenin is associated with RNA-binding protein HuR. Mol. Carcinog. 2009; 48:118–129. PubMed PMC

Nakamura H., Kawagishi H., Watanabe A., Sugimoto K., Maruyama M., Sugimoto M.. Cooperative role of the RNA-binding proteins Hzf and HuR in p53 activation. Mol. Cell Biol. 2011; 31:1997–2009. PubMed PMC

Abdelmohsen K., Panda A.C., Kang M.J., Guo R., Kim J., Grammatikakis I., Yoon J.H., Dudekula D.B., Noh J.H., Yang X. et al. .. 7SL RNA represses p53 translation by competing with HuR. Nucleic Acids Res. 2014; 42:10099–10111. PubMed PMC

Li Y., Gordon M.W., Xu-Monette Z.Y., Visco C., Tzankov A., Zou D., Qiu L., Montes-Moreno S., Dybkaer K., Orazi A. et al. .. Single nucleotide variation in the TP53 3′ untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013; 121:4529–4540. PubMed PMC

Ahuja D., Goyal A., Ray P.S.. Interplay between RNA-binding protein HuR and microRNA-125b regulates p53 mRNA translation in response to genotoxic stress. RNA Biol. 2016; 13:1152–1165. PubMed PMC

Kim B.C., Lee H.C., Lee J.J., Choi C.M., Kim D.K., Lee J.C., Ko Y.G., Lee J.S.. Wig1 prevents cellular senescence by regulating p21 mRNA decay through control of RISC recruitment. EMBO J. 2012; 31:4289–4303. PubMed PMC

Bersani C., Xu L.D., Vilborg A., Lui W.O., Wiman K.G.. Wig-1 regulates cell cycle arrest and cell death through the p53 targets FAS and 14-3-3sigma. Oncogene. 2014; 33:4407–4417. PubMed PMC

Vilborg A., Glahder J.A., Wilhelm M.T., Bersani C., Corcoran M., Mahmoudi S., Rosenstierne M., Grander D., Farnebo M., Norrild B. et al. .. The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element. Proc. Natl. Acad. Sci. U.S.A. 2009; 106:15756–15761. PubMed PMC

Prahl M., Vilborg A., Palmberg C., Jornvall H., Asker C., Wiman K.G.. The p53 target protein Wig-1 binds hnRNP A2/B1 and RNA Helicase A via RNA. FEBS Lett. 2008; 582:2173–2177. PubMed

Devany E., Zhang X., Park J.Y., Tian B., Kleiman F.E.. Positive and negative feedback loops in the p53 and mRNA 3′ processing pathways. Proc. Natl. Acad. Sci. U.S.A. 2013; 110:3351–3356. PubMed PMC

Zhang X., Devany E., Murphy M.R., Glazman G., Persaud M., Kleiman F.E.. PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells. Nucleic Acids Res. 2015; 43:10925–10938. PubMed PMC

Zhang L.N., Yan Y.B.. Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression. Biochim. Biophys. Acta. 2015; 1853:522–534. PubMed

Rosenstierne M.W., Vinther J., Mittler G., Larsen L., Mann M., Norrild B.. Conserved CPEs in the p53 3′ untranslated region influence mRNA stability and protein synthesis. Anticancer Res. 2008; 28:2553–2559. PubMed

Mazan-Mamczarz K., Kuwano Y., Zhan M., White E.J., Martindale J.L., Lal A., Gorospe M.. Identification of a signature motif in target mRNAs of RNA-binding protein AUF1. Nucleic Acids Res. 2009; 37:204–214. PubMed PMC

Fernandez-Miranda G., Mendez R.. The CPEB-family of proteins, translational control in senescence and cancer. Ageing Res. Rev. 2012; 11:460–472. PubMed

Burns D.M., Richter J.D.. CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation. Genes Dev. 2008; 22:3449–3460. PubMed PMC

Burns D.M., D’Ambrogio A., Nottrott S., Richter J.D.. CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation. Nature. 2011; 473:105–108. PubMed PMC

Schumacher B., Hanazawa M., Lee M.H., Nayak S., Volkmann K., Hofmann E.R., Hengartner M., Schedl T., Gartner A.. Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis. Cell. 2005; 120:357–368. PubMed

Zhang J., Cho S.J., Shu L., Yan W., Guerrero T., Kent M., Skorupski K., Chen H., Chen X.. Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas. Genes Dev. 2011; 25:1528–1543. PubMed PMC

Zhang M., Zhang J., Chen X., Cho S.J.. Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1. Genes Dev. 2013; 27:2246–2258. PubMed PMC

Zhang M., Xu E., Zhang J., Chen X.. PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38. Oncogene. 2015; 34:5900–5911. PubMed PMC

Zhang J., Xu E., Ren C., Yan W., Zhang M., Chen M., Cardiff R.D., Imai D.M., Wisner E., Chen X.. Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors. Proc. Natl. Acad. Sci. U.S.A. 2014; 111:18637–18642. PubMed PMC

Zhang J., Jun Cho S., Chen X.. RNPC1, an RNA-binding protein and a target of the p53 family, regulates p63 expression through mRNA stability. Proc. Natl. Acad. Sci. U.S.A. 2010; 107:9614–9619. PubMed PMC

Protter D.S., Parker R.. Principles and Properties of Stress Granules. Trends Cell Biol. 2016; 26:668–679. PubMed PMC

Diaz-Munoz M.D., Kiselev V.Y., Le Novere N., Curk T., Ule J., Turner M.. Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells. Nat. Commun. 2017; 8:530. PubMed PMC

Decorsiere A., Cayrel A., Vagner S., Millevoi S.. Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage. Genes Dev. 2011; 25:220–225. PubMed PMC

Newman M., Sfaxi R., Saha A., Monchaud D., Teulade-Fichou M.P., Vagner S.. The G-Quadruplex-Specific RNA helicase DHX36 regulates p53 Pre-mRNA 3′-End processing following UV-Induced DNA damage. J. Mol. Biol. 2017; 429:3121–3131. PubMed

Hu W., Chan C.S., Wu R., Zhang C., Sun Y., Song J.S., Tang L.H., Levine A.J., Feng Z.. Negative regulation of tumor suppressor p53 by microRNA miR-504. Mol. Cell. 2010; 38:689–699. PubMed PMC

Herrera-Merchan A., Cerrato C., Luengo G., Dominguez O., Piris M.A., Serrano M., Gonzalez S.. miR-33-mediated downregulation of p53 controls hematopoietic stem cell self-renewal. Cell Cycle. 2010; 9:3277–3285. PubMed

Swarbrick A., Woods S.L., Shaw A., Balakrishnan A., Phua Y., Nguyen A., Chanthery Y., Lim L., Ashton L.J., Judson R.L. et al. .. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat. Med. 2010; 16:1134–1140. PubMed PMC

Liu J., Zhang C., Zhao Y., Feng Z.. MicroRNA control of p53. J. Cell. Biochem. 2017; 118:7–14. PubMed

Katoch A., George B., Iyyappan A., Khan D., Das S.. Interplay between PTB and miR-1285 at the p53 3′UTR modulates the levels of p53 and its isoform Delta40p53alpha. Nucleic Acids Res. 2017; 45:10206–10217. PubMed PMC

Chaudhary R., Lal A.. Long noncoding RNAs in the p53 network. Wiley Interdiscip. Rev. RNA. 2017; 8:e1410–e1416. PubMed PMC

Mosner J., Mummenbrauer T., Bauer C., Sczakiel G., Grosse F., Deppert W.. Negative feedback regulation of wild-type p53 biosynthesis. EMBO J. 1995; 14:4442–4449. PubMed PMC

Takagi M., Absalon M.J., McLure K.G., Kastan M.B.. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell. 2005; 123:49–63. PubMed

Chen J., Kastan M.B.. 5′-3′-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. Genes Dev. 2010; 24:2146–2156. PubMed PMC

Chen J., Guo K., Kastan M.B.. Interactions of nucleolin and ribosomal protein L26 (RPL26) in translational control of human p53 mRNA. J. Biol. Chem. 2012; 287:16467–16476. PubMed PMC

Vagner S., Galy B., Pyronnet S.. Irresistible IRES. Attracting the translation machinery to internal ribosome entry sites. EMBO Rep. 2001; 2:893–898. PubMed PMC

Macejak D.G., Sarnow P.. Internal initiation of translation mediated by the 5′ leader of a cellular mRNA. Nature. 1991; 353:90–94. PubMed

Yang D.Q., Halaby M.J., Zhang Y.. The identification of an internal ribosomal entry site in the 5′-untranslated region of p53 mRNA provides a novel mechanism for the regulation of its translation following DNA damage. Oncogene. 2006; 25:4613–4619. PubMed

Ray P.S., Grover R., Das S.. Two internal ribosome entry sites mediate the translation of p53 isoforms. EMBO Rep. 2006; 7:404–410. PubMed PMC

Grover R., Candeias M.M., Fahraeus R., Das S.. p53 and little brother p53/47: linking IRES activities with protein functions. Oncogene. 2009; 28:2766–2772. PubMed

Khan D., Sharathchandra A., Ponnuswamy A., Grover R., Das S.. Effect of a natural mutation in the 5′ untranslated region on the translational control of p53 mRNA. Oncogene. 2013; 32:4148–4159. PubMed

Wedeken L., Singh P., Klempnauer K.H.. Tumor suppressor protein Pdcd4 inhibits translation of p53 mRNA. J. Biol. Chem. 2011; 286:42855–42862. PubMed PMC

Kim D.Y., Kim W., Lee K.H., Kim S.H., Lee H.R., Kim H.J., Jung Y., Choi J.H., Kim K.T.. hnRNP Q regulates translation of p53 in normal and stress conditions. Cell Death Differ. 2013; 20:226–234. PubMed PMC

Halaby M.J., Li Y., Harris B.R., Jiang S., Miskimins W.K., Cleary M.P., Yang D.Q.. Translational control protein 80 stimulates IRES-Mediated translation of p53 mRNA in response to DNA damage. Biomed Res. Int. 2015; 2015:708158. PubMed PMC

Xu Y.H., Busald C., Grabowski G.A.. Reconstitution of TCP80/NF90 translation inhibition activity in insect cells. Mol. Genet. Metab. 2000; 70:106–115. PubMed

Lamaa A., Le Bras M., Skuli N., Britton S., Frit P., Calsou P., Prats H., Cammas A., Millevoi S.. A novel cytoprotective function for the DNA repair protein Ku in regulating p53 mRNA translation and function. EMBO Rep. 2016; 17:508–518. PubMed PMC

Seo J.Y., Kim D.Y., Kim S.H., Kim H.J., Ryu H.G., Lee J., Lee K.H., Kim K.T.. Heterogeneous nuclear ribonucleoprotein (hnRNP) L promotes DNA damage-induced cell apoptosis by enhancing the translation of p53. Oncotarget. 2017; 8:51108–51122. PubMed PMC

Mahmoudi S., Henriksson S., Corcoran M., Mendez-Vidal C., Wiman K.G., Farnebo M.. Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol. Cell. 2009; 33:462–471. PubMed

Blaszczyk L., Ciesiolka J.. Secondary structure and the role in translation initiation of the 5′-terminal region of p53 mRNA. Biochemistry. 2011; 50:7080–7092. PubMed

Swiatkowska A., Zydowicz P., Sroka J., Ciesiolka J.. The role of the 5′ terminal region of p53 mRNA in the p53 gene expression. Acta Biochim. Pol. 2016; 63:645–651. PubMed

Fahraeus R., Marin M., Olivares-Illana V.. Whisper mutations: cryptic messages within the genetic code. Oncogene. 2016; 35:3753–3759. PubMed

Candeias M.M., Powell D.J., Roubalova E., Apcher S., Bourougaa K., Vojtesek B., Bruzzoni-Giovanelli H., Fahraeus R.. Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation. Oncogene. 2006; 25:6936–6947. PubMed

Grover R., Ray P.S., Das S.. Polypyrimidine tract binding protein regulates IRES-mediated translation of p53 isoforms. Cell Cycle. 2008; 7:2189–2198. PubMed

Sharathchandra A., Lal R., Khan D., Das S.. Annexin A2 and PSF proteins interact with p53 IRES and regulate translation of p53 mRNA. RNA Biol. 2012; 9:1429–1439. PubMed

Henis-Korenblit S., Strumpf N.L., Goldstaub D., Kimchi A.. A novel form of DAP5 protein accumulates in apoptotic cells as a result of caspase cleavage and internal ribosome entry site-mediated translation. Mol. Cell Biol. 2000; 20:496–506. PubMed PMC

Weingarten-Gabbay S., Khan D., Liberman N., Yoffe Y., Bialik S., Das S., Oren M., Kimchi A.. The translation initiation factor DAP5 promotes IRES-driven translation of p53 mRNA. Oncogene. 2014; 33:611–618. PubMed

Chu E., Voeller D.M., Jones K.L., Takechi T., Maley G.F., Maley F., Segal S., Allegra C.J.. Identification of a thymidylate synthase ribonucleoprotein complex in human colon cancer cells. Mol. Cell Biol. 1994; 14:207–213. PubMed PMC

Chu E., Copur S.M., Ju J., Chen T.M., Khleif S., Voeller D.M., Mizunuma N., Patel M., Maley G.F., Maley F. et al. .. Thymidylate synthase protein and p53 mRNA form an in vivo ribonucleoprotein complex. Mol. Cell Biol. 1999; 19:1582–1594. PubMed PMC

Bourougaa K., Naski N., Boularan C., Mlynarczyk C., Candeias M.M., Marullo S., Fahraeus R.. Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol. Cell. 2010; 38:78–88. PubMed

Hetz C., Papa F.R.. The Unfolded Protein Response and Cell Fate Control. Mol. Cell. 2018; 69:169–181. PubMed

Zhang K., Kaufman R.J.. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology. 2006; 66:S102–S109. PubMed

Jiang Q., Li F., Shi K., Wu P., An J., Yang Y., Xu C.. Involvement of p38 in signal switching from autophagy to apoptosis via the PERK/eIF2alpha/ATF4 axis in selenite-treated NB4 cells. Cell Death Dis. 2014; 5:e1270. PubMed PMC

Mlynarczyk C., Fahraeus R.. Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21(CDKN1A). Nat. Commun. 2014; 5:5067. PubMed

Pyronnet S., Pradayrol L., Sonenberg N.. A cell cycle-dependent internal ribosome entry site. Mol. Cell. 2000; 5:607–616. PubMed

Lopez I., Tournillon A.S., Prado Martins R., Karakostis K., Malbert-Colas L., Nylander K., Fahraeus R.. p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress. Cell Death Differ. 2017; 24:1717–1729. PubMed PMC

Maier B., Gluba W., Bernier B., Turner T., Mohammad K., Guise T., Sutherland A., Thorner M., Scrable H.. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 2004; 18:306–319. PubMed PMC

Pehar M., Ko M.H., Li M., Scrable H., Puglielli L.. P44, the ‘longevity-assurance’ isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion. Aging Cell. 2014; 13:449–456. PubMed PMC

Li M., Pehar M., Liu Y., Bhattacharyya A., Zhang S.C., O’Riordan K.J., Burger C., D’Adamio L., Puglielli L.. The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism. Neurobiol. Aging. 2015; 36:2725–2736. PubMed PMC

Lee V.M., Goedert M., Trojanowski J.Q.. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 2001; 24:1121–1159. PubMed

Mironov A.S., Gusarov I., Rafikov R., Lopez L.E., Shatalin K., Kreneva R.A., Perumov D.A., Nudler E.. Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell. 2002; 111:747–756. PubMed

Garst A.D., Edwards A.L., Batey R.T.. Riboswitches: structures and mechanisms. Cold Spring Harb. Perspect. Biol. 2011; 3:a003533. PubMed PMC

Winkler W.C., Cohen-Chalamish S., Breaker R.R.. An mRNA structure that controls gene expression by binding FMN. Proc. Natl. Acad. Sci. U.S.A. 2002; 99:15908–15913. PubMed PMC

Winkler W.C., Breaker R.R.. Genetic control by metabolite-binding riboswitches. ChemBioChem. 2003; 4:1024–1032. PubMed

Winkler W., Nahvi A., Breaker R.R.. Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Nature. 2002; 419:952–956. PubMed

Mandal M., Boese B., Barrick J.E., Winkler W.C., Breaker R.R.. Riboswitches control fundamental biochemical pathways in Bacillus subtilis and other bacteria. Cell. 2003; 113:577–586. PubMed

Serganov A., Nudler E.. A decade of riboswitches. Cell. 2013; 152:17–24. PubMed PMC

Gajjar M., Candeias M.M., Malbert-Colas L., Mazars A., Fujita J., Olivares-Illana V., Fahraeus R.. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage. Cancer Cell. 2012; 21:25–35. PubMed

Malbert-Colas L., Ponnuswamy A., Olivares-Illana V., Tournillon A.S., Naski N., Fahraeus R.. HDMX folds the nascent p53 mRNA following activation by the ATM kinase. Mol. Cell. 2014; 54:500–511. PubMed

Candeias M.M., Malbert-Colas L., Powell D.J., Daskalogianni C., Maslon M.M., Naski N., Bourougaa K., Calvo F., Fahraeus R.. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat. Cell Biol. 2008; 10:1098–1105. PubMed

Karakostis K., Ponnuswamy A., Fusee L.T., Bailly X., Laguerre L., Worall E., Vojtesek B., Nylander K., Fahraeus R.. p53 mRNA and p53 Protein Structures Have Evolved Independently to Interact with MDM2. Mol. Biol. Evol. 2016; 33:1280–1292. PubMed

Skripkin E.A., Adhin M.R., de Smit M.H., van Duin J.. Secondary structure of the central region of bacteriophage MS2 RNA. Conservation and biological significance. J. Mol. Biol. 1990; 211:447–463. PubMed

Kortmann J., Narberhaus F.. Bacterial RNA thermometers: molecular zippers and switches. Nat. Rev. Microbiol. 2012; 10:255–265. PubMed

Meyer M., Plass M., Perez-Valle J., Eyras E., Vilardell J.. Deciphering 3′ss selection in the yeast genome reveals an RNA thermosensor that mediates alternative splicing. Mol. Cell. 2011; 43:1033–1039. PubMed

Meyer E., Aglyamova G.V., Matz M.V.. Profiling gene expression responses of coral larvae (Acropora millepora) to elevated temperature and settlement inducers using a novel RNA-Seq procedure. Mol. Ecol. 2011; 20:3599–3616. PubMed

Vandivier L., Li F., Zheng Q., Willmann M., Chen Y., Gregory B.. Arabidopsis mRNA secondary structure correlates with protein function and domains. Plant Signal Behav. 2013; 8:e24301. PubMed PMC

Marz M., Vanzo N., Stadler P.F.. Temperature-dependent structural variability of RNAs: spliced leader RNAs and their evolutionary history. J. Bioinform. Comput. Biol. 2010; 8:1–17. PubMed

Zilberstein D., Shapira M.. The role of pH and temperature in the development of Leishmania parasites. Annu. Rev. Microbiol. 1994; 48:449–470. PubMed

Close A. Development by degrees. Nurs. Stand. 1999; 13:59. PubMed

Bellas J., Beiras R., Vazquez E.. A standardisation of Ciona intestinalis (Chordata, Ascidiacea) embryo-larval bioassay for ecotoxicological studies. Water Res. 2003; 37:4613–4622. PubMed

Boley N., Stoiber M.H., Booth B.W., Wan K.H., Hoskins R.A., Bickel P.J., Celniker S.E., Brown J.B.. Genome-guided transcript assembly by integrative analysis of RNA sequence data. Nat. Biotechnol. 2014; 32:341–346. PubMed PMC

Zhang B., Rotelli M., Dixon M., Calvi B.R.. The function of Drosophila p53 isoforms in apoptosis. Cell Death Differ. 2015; 22:2058–2067. PubMed PMC

de Mendoza A., Sebe-Pedros A., Sestak M.S., Matejcic M., Torruella G., Domazet-Loso T., Ruiz-Trillo I.. Transcription factor evolution in eukaryotes and the assembly of the regulatory toolkit in multicellular lineages. Proc. Natl. Acad. Sci. U.S.A. 2013; 110:E4858–E4866. PubMed PMC

Chen K., Rajewsky N.. The evolution of gene regulation by transcription factors and microRNAs. Nat. Rev. Genet. 2007; 8:93–103. PubMed

Dunker A.K., Cortese M.S., Romero P., Iakoucheva L.M., Uversky V.N.. Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 2005; 272:5129–5148. PubMed

Joerger A.C., Wilcken R., Andreeva A.. Tracing the evolution of the p53 tetramerization domain. Structure. 2014; 22:1301–1310. PubMed PMC

Huart A.S., Hupp T.R.. Evolution of conformational disorder & diversity of the P53 interactome. Bio. Discov. 2013; 8:e8952.

Watts J.M., Dang K.K., Gorelick R.J., Leonard C.W., Bess J.W. Jr, Swanstrom R., Burch C.L., Weeks K.M.. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature. 2009; 460:711–716. PubMed PMC

Nagata S., Imai J., Makino G., Tomita M., Kanai A.. Evolutionary analysis of HIV-1 pol proteins reveals representative residues for viral subtype differentiation. Front. Microbiol. 2017; 8:2151. PubMed PMC

Berkhout B. HIV-1 as RNA evolution machine. RNA Biol. 2011; 8:225–229. PubMed

Strazewski P., Biala E., Gabriel K., McClain W.H.. The relationship of thermodynamic stability at a G x U recognition site to tRNA aminoacylation specificity. RNA. 1999; 5:1490–1494. PubMed PMC

Sprinzl M., Steegborn C., Hubel F., Steinberg S.. Compilation of tRNA sequences and sequences of tRNA genes. Nucleic Acids Res. 1996; 24:68–72. PubMed PMC

Benard L., Mathy N., Grunberg-Manago M., Ehresmann B., Ehresmann C., Portier C.. Identification in a pseudoknot of a U.G motif essential for the regulation of the expression of ribosomal protein S15. Proc. Natl. Acad. Sci. U.S.A. 1998; 95:2564–2567. PubMed PMC

Li B., Vilardell J., Warner J.R.. An RNA structure involved in feedback regulation of splicing and of translation is critical for biological fitness. Proc. Natl. Acad. Sci. U.S.A. 1996; 93:1596–1600. PubMed PMC

Varani G., McClain W.H.. The G x U wobble base pair. A fundamental building block of RNA structure crucial to RNA function in diverse biological systems. EMBO Rep. 2000; 1:18–23. PubMed PMC

Hur M., Waring R.B.. Two group I introns with a C.G basepair at the 5′ splice-site instead of the very highly conserved U.G basepair: is selection post-translational. Nucleic Acids Res. 1995; 23:4466–4470. PubMed PMC

Ferre-D’Amare A.R., Zhou K., Doudna J.A.. Crystal structure of a hepatitis delta virus ribozyme. Nature. 1998; 395:567–574. PubMed

Jegga A.G., Inga A., Menendez D., Aronow B.J., Resnick M.A.. Functional evolution of the p53 regulatory network through its target response elements. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:944–949. PubMed PMC

Wang X., Wang J., Jiang X.. MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J. Biol. Chem. 2011; 286:23725–23734. PubMed PMC

Wang X., Jiang X.. Mdm2 and MdmX partner to regulate p53. FEBS Lett. 2012; 586:1390–1396. PubMed

Zhang Q., Zeng S.X., Lu H.. Targeting p53-MDM2-MDMX loop for cancer therapy. Subcell. Biochem. 2014; 85:281–319. PubMed PMC

Medina-Medina I., Garcia-Beltran P., de la Mora-de la Mora I., Oria-Hernandez J., Millot G., Fahraeus R., Reyes-Vivas H., Sampedro J.G., Olivares-Illana V.. Allosteric interactions by p53 mRNA governs HDM2 E3 ubiquitin ligase specificity under different conditions. Mol. Cell Biol. 2016; 36:2195–205. PubMed PMC

Montes de Oca Luna R., Wagner D.S., Lozano G.. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995; 378:203–206. PubMed

Parant J., Chavez-Reyes A., Little N.A., Yan W., Reinke V., Jochemsen A.G., Lozano G.. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat. Genet. 2001; 29:92–95. PubMed

Pant V., Lozano G.. Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity. Oncotarget. 2014; 5:1149–1156. PubMed PMC

Maya R., Balass M., Kim S.T., Shkedy D., Leal J.F., Shifman O., Moas M., Buschmann T., Ronai Z., Shiloh Y. et al. .. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 2001; 15:1067–1077. PubMed PMC

Medina-Medina I., Martinez-Sanchez M., Hernandez-Monge J., Fahraeus R., Muller P., Olivares-Illana V.. p53 promotes its own polyubiquitination by enhancing the HDM2 and HDMX interaction. Protein Sci. 2018; 27:976–986. PubMed PMC

Pereg Y., Shkedy D., de Graaf P., Meulmeester E., Edelson-Averbukh M., Salek M., Biton S., Teunisse A.F., Lehmann W.D., Jochemsen A.G. et al. .. Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proc. Natl. Acad. Sci. U.S.A. 2005; 102:5056–5061. PubMed PMC

Nissley D.A., O’Brien E.P.. Timing is everything: unifying codon translation rates and nascent proteome behavior. J. Am. Chem. Soc. 2014; 136:17892–17898. PubMed

Oscier D.G., Gardiner A.C., Mould S.J., Glide S., Davis Z.A., Ibbotson R.E., Corcoran M.M., Chapman R.M., Thomas P.W., Copplestone J.A. et al. .. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002; 100:1177–1184. PubMed

Kanjilal S., Strom S.S., Clayman G.L., Weber R.S., el-Naggar A.K., Kapur V., Cummings K.K., Hill L.A., Spitz M.R., Kripke M.L. et al. .. p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization. Cancer Res. 1995; 55:3604–3609. PubMed

Hayes V.M., Bleeker W., Verlind E., Timmer T., Karrenbeld A., Plukker J.T., Marx M.P., Hofstra R.M., Buys C.H.. Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection assay also applicable to archival paraffin-embedded tissue. Diagn. Mol. Pathol. 1999; 8:2–10. PubMed

Karakostis K., Vadivel Gnanasundram S., Lopez I., Thermou A., Wang L., Nylander K., Olivares-Illana V., Fahraeus R.. A single synonymous mutation determines the phosphorylation and stability of the nascent protein. J. Mol. Cell Biol. 2018; doi:10.1093/jmcb/mjy049. PubMed PMC

Buchan J.R., Stansfield I.. Halting a cellular production line: responses to ribosomal pausing during translation. Biol. Cell. 2007; 99:475–487. PubMed

Cortazzo P., Cervenansky C., Marin M., Reiss C., Ehrlich R., Deana A.. Silent mutations affect in vivo protein folding in Escherichia coli. Biochem. Biophys. Res. Commun. 2002; 293:537–541. PubMed

Sauna Z.E., Kimchi-Sarfaty C.. Understanding the contribution of synonymous mutations to human disease. Nat. Rev. Genet. 2011; 12:683–691. PubMed

Gartner J.J., Parker S.C., Prickett T.D., Dutton-Regester K., Stitzel M.L., Lin J.C., Davis S., Simhadri V.L., Jha S., Katagiri N. et al. .. Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma. Proc. Natl. Acad. Sci. U.S.A. 2013; 110:13481–13486. PubMed PMC

Zheng S., Kim H., Verhaak R.G.. Silent mutations make some noise. Cell. 2014; 156:1129–1131. PubMed

Supek F., Minana B., Valcarcel J., Gabaldon T., Lehner B.. Synonymous mutations frequently act as driver mutations in human cancers. Cell. 2014; 156:1324–1335. PubMed

Unger T., Sionov R.V., Moallem E., Yee C.L., Howley P.M., Oren M., Haupt Y.. Mutations in serines 15 and 20 of human p53 impair its apoptotic activity. Oncogene. 1999; 18:3205–3212. PubMed

Wallingford J.B., Seufert D.W., Virta V.C., Vize P.D.. p53 activity is essential for normal development in Xenopus. Curr. Biol. 1997; 7:747–757. PubMed

Levrero M., De Laurenzi V., Costanzo A., Gong J., Wang J.Y., Melino G.. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J. Cell Sci. 2000; 113:1661–1670. PubMed

Moll U.M., Petrenko O.. The MDM2-p53 interaction. Mol. Cancer Res. 2003; 1:1001–1008. PubMed

Maclaine N.J., Hupp T.R.. The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway. Aging (Albany NY). 2009; 1:490–502. PubMed PMC

Harms K.L., Chen X.. The functional domains in p53 family proteins exhibit both common and distinct properties. Cell Death Differ. 2006; 13:890–897. PubMed

Craig A., Scott M., Burch L., Smith G., Ball K., Hupp T.. Allosteric effects mediate CHK2 phosphorylation of the p53 transactivation domain. EMBO Rep. 2003; 4:787–792. PubMed PMC

Xirodimas D.P., Stephen C.W., Lane D.P.. Cocompartmentalization of p53 and Mdm2 is a major determinant for Mdm2-mediated degradation of p53. Exp. Cell Res. 2001; 270:66–77. PubMed

Re-appraising the evidence for the source, regulation and function of p53-family isoforms

The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

p53 mRNA Metabolism Links with the DNA Damage Response

Molecular and Biochemical Techniques for Deciphering p53-MDM2 Regulatory Mechanisms

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures