miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-Prone DSB Repair.

UNLABELLED: miR-155 is an oncogenic miRNA that is often overexpressed in cancer and is associated with poor prognosis. miR-155 can target several DNA repair factors, including RAD51, MLH1, and MSH6, and its overexpression results in an increased mutation frequency in vitro, although the mechanism has yet to be fully understood. Here, we demonstrate that overexpression of miR-155 drives an increased mutation frequency both in vitro and in vivo, promoting genomic instability by affecting multiple DNA repair pathways. miR-155 overexpression causes a decrease in homologous recombination, but yields a concurrent increase in the error-prone nonhomologous end-joining pathway. Despite repressing established targets MLH1 and MSH6, the identified mutation pattern upon miR-155 overexpression does not resemble that of a mismatch repair-deficient background. Further investigation revealed that all four subunits of polymerase delta, a high-fidelity DNA replication, and repair polymerase are downregulated at the mRNA level in the context of miR-155 overexpression. FOXO3a, a transcription factor and known target of miR-155, has one or more putative binding site(s) in the promoter of all four polymerase delta subunits. Finally, suppression of FOXO3a by miR-155 or by siRNA knockdown is sufficient to repress the expression of the catalytic subunit of polymerase delta, POLD1, at the protein level, indicating that FOXO3a contributes to the regulation of polymerase delta levels. IMPLICATIONS: Taken together, miR-155 overexpression drives an increase in mutation frequency via multifaceted impact on DNA damage response and DNA repair pathways.

microRNAs in cancer cell response to ionizing radiation.

SIGNIFICANCE: microRNAs (miRNA) have been characterized as master regulators of the genome. As such, miRNAs are responsible for regulating almost every cellular pathway, including the DNA damage response (DDR) after ionizing radiation (IR). IR is a therapeutic tool that is used for the treatment of several types of cancer, yet the mechanism behind radiation response is not fully understood. RECENT ADVANCES: It has been demonstrated that IR can alter miRNA expression profiles, varying greatly from one cell type to the next. It is possible that this variation contributes to the range of tumor cell responsiveness that is observed after radiotherapy, especially considering the extensive role for miRNAs in regulating the DDR. In addition, individual miRNAs or miRNA families have been shown to play a multifaceted role in the DDR, regulating multiple members in a single pathway. CRITICAL ISSUES: In this review, we will discuss the effects of radiation on miRNA expression as well as explore the function of miRNAs in regulating the cellular response to radiation-induced damage. We will discuss the importance of miRNA regulation at each stage of the DDR, including signal transduction, DNA damage sensing, cell cycle checkpoint activation, DNA double-strand break repair, and apoptosis. We will focus on emphasizing the importance of a single miRNA targeting several mediators within a pathway. FUTURE DIRECTIONS: miRNAs will continue to emerge as critical regulators of the DDR. Understanding the role of miRNAs in the response to IR will provide insights for improving the current standard therapy.