期刊
CELL CYCLE
卷 13, 期 16, 页码 2572-2586出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/15384101.2015.942209
关键词
p53; micro-RNA; DNA damage response; next-generation sequencing; computational analysis; clinical outcome; DDR; DNA damage response; miRNA; micro-RNA; NGS; next-generation sequencing; TP53; tumour protein p53; NF-k B; nuclear factor-k B; AP-1; activator protein-1; E2F1; transcription factor E2F1; FoxM1; forkhead box protein M1; ionizing radiation; IR; double stranded DNA breaks; DSBs; tRNA; transfer RNA; snoRNA; small nucleolar RNA; scRNA; small cytoplasmic RNA; snRNA; small nuclear RNA; misc RNA; miscellaneous RNA; TF; transcription factor
类别
资金
- Medical Research Council (MRC)
- MRC
- European Union
- MRC [MC_UU_12022/8, MC_U105359877, MC_UU_12022/1, G1001522, G1001521, MC_U105185859] Funding Source: UKRI
- Medical Research Council [MC_UU_12022/1, MC_U105359877, G1001522, MC_U105185859, G1001521] Funding Source: researchfish
The human DNA damage response (DDR) triggers profound changes in gene expression, whose nature and regulation remain uncertain. Although certain micro-(mi)RNA species including miR34, miR-18, miR-16 and miR-143 have been implicated in the DDR, there is as yet no comprehensive description of genome-wide changes in the expression of miRNAs triggered by DNA breakage in human cells. We have used next-generation sequencing (NGS), combined with rigorous integrative computational analyses, to describe genome-wide changes in the expression of miRNAs during the human DDR. The changes affect 150 of 1523 miRNAs known in miRBase v18 from 4-24h after the induction of DNA breakage, in cell-type dependent patterns. The regulatory regions of the most-highly regulated miRNA species are enriched in conserved binding sites for p53. Indeed, genome-wide changes in miRNA expression during the DDR are markedly altered in TP53-/- cells compared to otherwise isogenic controls. The expression levels of certain damage-induced, p53-regulated miRNAs in cancer samples correlate with patient survival. Our work reveals genome-wide and cell type-specific alterations in miRNA expression during the human DDR, which are regulated by the tumor suppressor protein p53. These findings provide a genomic resource to identify new molecules and mechanisms involved in the DDR, and to examine their role in tumor suppression and the clinical outcome of cancer patients.
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