p53 shapes genome-wide and cell type-specific changes in microRNA expression during the human DNA damage response.

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Hattori, Hiroyoshi 
Janky, Rekin's 
Nietfeld, Wilfried 
Madan Babu, M 

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 4-24 h 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.

AP-1, activator protein-1, DDR, DNA damage response, DNA damage response, E2F1, transcription factor E2F1, FoxM1, forkhead box protein M1, NF-k B, nuclear factor-k B, NGS, next-generation sequencing, TF, transcription factor, TP53, tumour protein p53, clinical outcome, computational analysis, double stranded DNA breaks, DSBs, ionizing radiation, IR, miRNA, micro-RNA, micro-RNA, misc RNA, miscellaneous RNA, next-generation sequencing, p53, scRNA, small cytoplasmic RNA, snRNA, small nuclear RNA, snoRNA, small nucleolar RNA, tRNA, transfer RNA, Cell Line, DNA Damage, DNA Repair, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Genome, Genome, Human, Humans, MicroRNAs, Neoplasms, Organ Specificity, Tumor Suppressor Protein p53
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Cell Cycle
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Informa UK Limited
Medical Research Council (G1001521)
Medical Research Council (G1001522)
Medical Research Council (MC_UU_12022/1)
MRC (MC_UU_12022/8)