Trends in Biochemical Sciences
ReviewmiRNA response to DNA damage
Section snippets
Canonical DNA damage response
DNA damage in cells is caused by intrinsic and extrinsic genotoxic stresses, including ultraviolet light (UV), ionizing radiation (IR), chemo- and radiotherapeutic agents, and reactive oxygen species. DNA damage response is a functional network combining signal transduction, cell cycle regulation and DNA repair, which is conserved in many aspects from yeast to humans [1]. DNA damage response is initiated by early signaling events, including activation of the phosphoinositide-3 kinase
miRNA expression and maturation
The DNA damage response involves a complex network of processes that detect and repair DNA damage, in which miRNAs, a class of small regulatory RNAs, could play important roles. However, very little is known about whether and how miRNA expression is regulated in the DNA damage response. To dissect mechanisms by which miRNA expression is regulated, it is important to first understand how miRNAs are transcribed and processed (Figure 1a). miRNAs are an evolutionarily conserved group of small
miRNAs regulate DNA damage response through target genes
In addition to being regulated by the canonical signaling pathways, increasing evidence shows that the DNA damage response is also epigenetically regulated. First, the chromatin structure needs to be reorganized to accommodate the binding of the involved transcription factors in gene transcription and replication. During DNA repair, chromatin remodeling occurs to allow DNA repair proteins to reach damaged DNA. Two mechanisms are involved in the chromatin remodeling: post-translational histone
Regulation of miRNA expression in DNA damage response
Treatment with different types of DNA damaging agents has been shown to result in differential activation of miRNAs. Varying doses of DNA damage seemingly lead to activation of unique as well as common sets of miRNAs, suggesting that miRNAs regulate the DNA damage response by a mechanism based on the nature and intensity of DNA damage [34]. Although several DNA damage responsive miRNAs and their targets have been identified, many remain to be discovered. Complex interconnections between miRNAs
Transcriptional regulation of miRNA in DNA damage
DNA damage can regulate miRNA expression at the transcriptional level. Similar to regular genes, miRNA gene transcription is controlled by transcription factors. The tumor suppressor p53 is well known as a DNA damage-induced transcription factor. The first discovery connecting p53 to the regulation of miRNAs was the identification of the miR-34 family, a direct transcriptional target of p53, whereby induction by DNA damage and oncogenic stress pervades in diverse aspects of the DNA damage
Post-transcriptional regulation of miRNA in DNA damage
Equally as important as miRNA gene transcription, post-transcriptional processing of miRNAs is also regulated in the DNA damage response. We recently found that DNA damage led to increased levels of some pre-miRNAs and mature miRNAs without significant changes of levels of their primary transcripts, suggesting post-transcriptional mechanism(s) could contribute to the induction of certain miRNAs under DNA damage stress [41]. There appears to be functional connections between DNA damage response
Concluding remarks and future directions
Taken together, although several studies have shown that miRNA expression is regulated transcriptionally and post-transcriptionally in the DNA damage response, there are still many important questions to be addressed. In particular, it remains largely unknown how miRNA biogenesis responds to DNA damage for p53- or KSRP-independent miRNAs. There should be other potential mechanisms to account for the induction of those miRNAs. Further studies on the following aspects might provide insights into
Acknowledgments
X.L. is supported by a National Institutes of Health grant (CA136549), a research grant from the American Cancer Society (119135-RSG-10-185-01-TBE) and the University of Texas Systems STARS PLUS Award. We apologize to our colleagues whose work we could not cite owing to length constraints.
References (83)
ATM and ATR: networking cellular responses to DNA damage
Curr. Opin. Genet. Dev.
(2001)- et al.
The DNA damage response: making it safe to play with knives
Mol. Cell
(2010) Substrate specificities and identification of putative substrates of ATM kinase family members
J. Biol. Chem.
(1999)- et al.
P53 and prognosis: new insights and further complexity
Cell
(2005) MicroRNAs: target recognition and regulatory functions
Cell
(2009)MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)MicroRNA regulation of cell lineages in mouse and human embryonic stem cells
Cell Stem Cell
(2008)- et al.
Posttranscriptional regulation of microRNA biogenesis in animals
Mol. Cell
(2010) - et al.
Dual role for argonautes in microRNA processing and posttranscriptional regulation of microRNA expression
Cell
(2007) Argonaute2 cleaves the anti-guide strand of siRNA during RISC activation
Cell
(2005)
Nuclear networking fashions pre-messenger RNA and primary microRNA transcripts for function
Trends Cell Biol.
Negative regulation of tumor suppressor p53 by microRNA miR-504
Mol. Cell
Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development
Cancer Cell
The ATM kinase induces microRNA biogenesis in the DNA damage response
Mol. Cell
Stress granules: the Tao of RNA triage
Trends Biochem. Sci.
Phosphoproteomic analysis of human embryonic stem cells
Cell Stem Cell
A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells
Cancer Cell
E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer
Cancer Cell
miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors
Mol. Cell
An E2F/miR-20a autoregulatory feedback loop
J. Biol. Chem.
microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma
Blood
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
Science
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Nat. Rev. Cancer
MicroRNAs in cancer
Annu. Rev. Med.
Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma
Cancer Res.
Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers
Proc. Natl. Acad. Sci. U.S.A.
Emerging paradigms of regulated microRNA processing
Genes Dev.
MicroRNA genes are transcribed by RNA polymerase II
EMBO J.
Processing of intronic microRNAs
EMBO J.
The nuclear RNase III Drosha initiates microRNA processing
Nature
Nuclear export of microRNA precursors
Science
Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs
Genes Dev.
Many roads to maturity: microRNA biogenesis pathways and their regulation
Nat. Cell Biol.
Active turnover modulates mature microRNA activity in Caenorhabditis elegans
Nature
Human polynucleotide phosphorylase selectively and preferentially degrades microRNA-221 in human melanoma cells
Proc. Natl. Acad. Sci. U.S.A.
Chromatin dynamics coupled to DNA repair
Epigenetics
ATM is down-regulated by N-Myc-regulated microRNA-421
Proc. Natl. Acad. Sci. U.S.A.
miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells
Nat. Struct. Mol. Biol.
A microRNA component of the p53 tumour suppressor network
Nature
MicroRNA-125b is a novel negative regulator of p53
Genes Dev.
Immunofluorescence-based screening identifies germ cell associated microRNA 302 as an antagonist to p63 expression
Cell Cycle
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