Review
miRNA response to DNA damage

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Faithful transmission of genetic material in eukaryotic cells requires not only accurate DNA replication and chromosome distribution but also the ability to sense and repair spontaneous and induced DNA damage. To maintain genomic integrity, cells undergo a DNA damage response using a complex network of signaling pathways composed of coordinate sensors, transducers and effectors in cell cycle arrest, apoptosis and DNA repair. Emerging evidence has suggested that miRNAs play a crucial role in regulation of DNA damage response. In this review, we discuss the recent findings on how miRNAs interact with the canonical DNA damage response and how miRNA expression is regulated after 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.

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