title: MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells.
abstract: Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this article, we provide evidence that expression of p21 protein is directly regulated by the microRNA (miRNA) pathway under standard culture conditions and after DNA damage. The DDR in hESCs leads to upregulation of tens of miRNAs, including hESC-specific miRNAs such as those of the miR-302 family, miR-371-372 family, or C19MC miRNA cluster. Most importantly, we show that the hESC-enriched miRNA family miR-302 (miR-302a, miR-302b, miR-302c, and miR-302d) directly contributes to regulation of p21 expression in hESCs and, thus, demonstrate a novel function for miR-302s in hESCS. The described mechanism elucidates the role of miRNAs in regulation of important molecular pathway governing the G1/S transition checkpoint before as well as after DNA damage.
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 3/A1, Brno, Czech Republic.
authors.forename: Dasa
authors.initials: D
authors.lastname: Dolezalova
authors.forename: Marek
authors.initials: M
authors.lastname: Mraz
authors.forename: Tomas
authors.initials: T
authors.lastname: Barta
authors.forename: Karla
authors.initials: K
authors.lastname: Plevova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vinarsky
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Holubcova
authors.forename: Josef
authors.initials: J
authors.lastname: Jaros
authors.forename: Petr
authors.initials: P
authors.lastname: Dvorak
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.forename: Ales
authors.initials: A
authors.lastname: Hampl
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D035683:MicroRNAs / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53