MicroRNAs and DNA damage response: implications for cancer therapy

Abstract

The DNA damage response (DDR) pathways play critical roles in protecting the genome from DNA damage. Abrogation of DDR often results in elevated genomic instability and cellular sensitivity to DNA damaging agents. Many proteins involved in DDR are subjected to precise regulation at multiple levels, such as transcriptional control and posttranslational modifications, in response to DNA damage. MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. The expression levels of some miRNAs change in response to DNA damage. Some miRNAs, such as miR-24, 138, 96 and 182, have been implicated in DDR and/or DNA repair and affect cellular sensitivity to DNA damaging agents. In this review, we summarize recent findings related to the emerging roles of miRNAs in regulating DDR and DNA repair and discuss their potential in cancer therapy.

Figure 1. Canonical miRNA biogenesis and its regulation by interacting partners. MiRNAs genes are transcribed by RNA polymerases II or III (Pol II/III) into pri-miRNAs from intergenic or intronic regions. The pri-miRNAs are recognized and processed by the DROSHA-DGCR8 complex to generate pre-miRNAs, which are subsequently released into cytosol by the XPO5-containing nuclear export receptor complex. The cytosolic pre-miRNAs will be further digested by the Dicer-TRBP complex to produce miRNA duplexes, which are unwinded and incorporated into the RISC complex for target recognition and silencing. Single-stranded miRNA can be decayed by the 5′-3′ exoribonuclease XRN2 or 3′-5′ exoribonuclease human polynucleotide phosphrylase (hPNPase). The unprocessed pre-miRNAs can also bind to MCPIP1, leading to degradation of pre-miRNAs. The biogenesis of miRNA is subjected to regulation by many proteins that bind to either pri-miRNAs or pre-miRNAs (refer to text for details).

Figure 2. A proposed model for the roles of miRNAs in DDR. DNA damage triggers the activation of PI3K-like kinases, such as ATM. ATM phosphorylates a subset of substrates (i.e., p53, KSRP, BRCA1 and ΔNp63α), which activate the transcription of some miRNA genes or enhance their processing through regulating the interaction between miRNA processing complex and pri- or pre-miRNAs. Activation of PI3K-like kinases may also suppress the transcription or processing of some miRNAs through unknown mechanisms. Activation of PI3K-like kinase-independent pathways may also contribute to miRNA response upon DNA damage. The differentially expressed miRNAs may modulate DDR through regulating the expression of DDR/DNA repair genes or their regulatory factors.

Figure 3. Conceptual models of the functions of miRNAs in DDR. (A) Upregulated miRNAs in DDR may promote DDR by suppressing the negative regulators of DDR; (B) downregulated miRNAs in DDR may release their inhibitory roles on DDR by targeting positive regulators of DDR; (C) upregulated miRNAs in DDR may target positive regulators of DDR or downregulated miRNAs may target negative regulators of DDR to reach an optimal DDR or to shut off DNA repair once completed or in the case of extensive damage; (D) DNA damage may change the interaction between unaltered microRNAs and the positive or negative regulators of DDR/DNA repair. Examples for miRNAs and their targeting DDR regulators are shown in brackets.