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.
Keywords: 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.