miR-34a is a tumor suppressor in zebrafish and its expression levels impact metabolism, hematopoiesis and DNA damage.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

DNA Damage* ; Hematopoiesis*/genetics ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Tumor Suppressor Protein p53*/genetics ; Tumor Suppressor Protein p53*/metabolism ; Zebrafish*/genetics ; Zebrafish Proteins*/genetics ; Zebrafish Proteins*/metabolism; Animals ; Humans ; Mice ; Apoptosis/genetics ; Camptothecin/pharmacology ; Gene Expression Regulation, Developmental ; Genes, Tumor Suppressor ; Li-Fraumeni Syndrome/genetics

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Prykhozhij et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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XT3Z54Z28A (Camptothecin)
0 (MicroRNAs)
0 (tp53 protein, zebrafish)
0 (Tumor Suppressor Protein p53)
0 (Zebrafish Proteins)
0 (MIRN34 microRNA, zebrafish)

Date Created: 20240528 Date Completed: 20240611 Latest Revision: 20240711

20240712

PMC11166285

10.1371/journal.pgen.1011290

38805544