title: p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication.
abstract: The DNA damage response activates several pathways that stall the cell cycle and allow DNA repair. These consist of the well-characterized ATR (Ataxia telangiectasia and Rad-3 related)/CHK1 and ATM (Ataxia telangiectasia mutated)/CHK2 pathways in addition to a newly identified ATM/ATR/p38MAPK/MK2 checkpoint. Crucial to maintaining the integrity of the genome is the S-phase checkpoint that functions to prevent DNA replication until damaged DNA is repaired. Inappropriate expression of the proto-oncogene c-Myc is known to cause DNA damage. One mechanism by which c-Myc induces DNA damage is through binding directly to components of the prereplicative complex thereby promoting DNA synthesis, resulting in replication-associated DNA damage and checkpoint activation due to inappropriate origin firing. Here we show that following etoposide-induced DNA damage translation of c-Myc is repressed by miR-34c via a highly conserved target-site within the 3(') UTR. While miR-34c is induced by p53 following DNA damage, we show that in cells lacking p53 this is achieved by an alternative pathway which involves p38 MAPK signalling to MK2. The data presented here suggest that a major physiological target of miR-34c is c-Myc. Inhibition of miR-34c activity prevents S-phase arrest in response to DNA damage leading to increased DNA synthesis, DNA damage, and checkpoint activation in addition to that induced by etoposide alone, which are all reversed by subsequent c-Myc depletion. These data demonstrate that miR-34c is a critical regulator of the c-Myc expression following DNA damage acting downstream of p38 MAPK/MK2 and suggest that miR-34c serves to remove c-Myc to prevent inappropriate replication which may otherwise lead to genomic instability.
authors.affiliation: Center for Biomolecular Sciences, School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cannell
authors.forename: Yi W
authors.initials: YW
authors.lastname: Kong
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Johnston
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Chen
authors.forename: Hilary M
authors.initials: HM
authors.lastname: Collins
authors.forename: Helen C
authors.initials: HC
authors.lastname: Dobbyn
authors.forename: Androulla
authors.initials: A
authors.lastname: Elia
authors.forename: Theresia R
authors.initials: TR
authors.lastname: Kress
authors.forename: Martin
authors.initials: M
authors.lastname: Dickens
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemens
authors.forename: David M
authors.initials: DM
authors.lastname: Heery
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016196:S Phase / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D020413:3' Untranslated Regions; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C000715470:MAS1 protein, human; C522425:MIRN34 microRNA, human; C489427:MYC protein, human; C489428:Myc protein, mouse