MicroRNAs: new players in the DNA damage response

Abstract

The DNA damage response (DDR) is a signal transduction pathway that decides the cell's fate either to repair DNA damage or to undergo apoptosis if there is too much damage. Post-translational modifications modulate the assembly and activity of protein complexes during the DDR pathways. MicroRNAs (miRNAs) are emerging as a class of endogenous gene modulators that control protein levels, thereby adding a new layer of regulation to the DDR. In this review, we describe a new role for miRNAs in regulating the cellular response to DNA damage with a focus on DNA double-strand break damage. We also discuss the implications of miRNA's role in the DDR to stem cells, including embryonic stem cells and cancer stem cells, stressing the potential applications for miRNAs to be used as sensitizers for cancer radiotherapy and chemotherapy.

Figure 1

DNA damage affects the biogenesis of miRNAs. (A) DNA damage regulates specific miRNA's expression through transcription, and p53 is an exemplary transcription factor that mediates miRNAs’ transcription. (B) DNA damage also regulates a subset of miRNAs’ by modulating the processing and maturation of miRNA biogenesis. p53 could interact with the Drosha/DGCR8 complex through p68 helicase to enhance the miRNAs’ expression. (C) Whether DNA damage influences miRNAs expression by modulating the degradation step of miRNAs needs further investigation. The steps of miRNA biogenesis and degradation are described in more detail in the text.

Figure 2

miRNAs regulate DSB DDR through modulating the core protein components of various pathways. The key proteins during the DDR pathway are summarized in the order of sensors/mediators, transducers and effectors, while the effectors include DNA repair, cell-cycle checkpoint (G1/S, intra-S and G2/M) and apoptosis mechanisms. Interactions with miRNAs that regulate the expression of DDR protein components are indicated in red.