Li-Fraumeni 综合征是由遗传性 TP53 抑癌基因突变引起的。 MicroRNA miR-34a 是 p53 靶标和修饰基因。有趣的是，miR-34 三缺失小鼠表现出正常的 p53 反应，并且没有明显的癌症发展，但 miR-34 的缺乏会促进癌症易感背景中的肿瘤发生。 miR-34 基因在斑马鱼和人类之间高度保守且同线性。斑马鱼 miR-34a 和 miR-34b/c 在发育中具有相似的表达时间，但 miR-34a 更丰富。喜树碱造成的 DNA 损伤导致 miR-34 基因的 p53 依赖性诱导，而 miR-34a 突变体在成体中具有活力，并具有正常的 DNA 损伤诱导的细胞凋亡。然而，具有功能获得性tp53R217H/R217H或tp53-/-突变体的miR-34a-/-复合突变体比单独的tp53突变体更容易患癌症，证实了miR-34a的肿瘤抑制功能。通过受精后 28 小时 (hpf) 的转录组比较，我们表征了 DNA 损伤诱导的转录，并在 8、28 和 72 hpf 时确定了潜在的 miR-34a 调节基因。 72 hpf 时，miR-34a 的缺失增强了红细胞水平并上调了 myb 阳性造血干细胞。 miR-34a 的过度表达会抑制其报告基因 mRNA，但不会抑制 p53 靶标的诱导，并使注射的胚胎对喜树碱敏感，但不会对 γ 辐射敏感。版权所有：© 2024 Prykhozhij 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

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.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.