Involvement of miR-605 and miR-34a in the DNA damage response promotes apoptosis induction

Abstract

MicroRNAs are key regulators of gene expression at the posttranscriptional level. In this study, we focus on miR-605 and miR-34a, which are direct transcriptional targets of p53 and in turn enhance its tumor suppressor function by acting upstream and downstream of it, respectively. miR-605 promotes p53 activation by repressing the expression of mdm2, whereas miR-34a promotes p53-dependent apoptosis by suppressing the expression of antiapoptotic genes such as bcl-2. What roles they play in the p53-mediated DNA damage response is less well understood. Here, we develop a four-module model of the p53 network to investigate the effect of miR-605 and miR-34a on the cell-fate decision after ionizing radiation. Results of numerical simulation indicate that the cell fate is closely associated with network dynamics. The concentration of p53 undergoes few pulses in response to repairable DNA damage, or it first oscillates and then switches to high plateau levels after irreparable damage. The amplitude of p53 pulses rises to various extents depending on miR-605 expression, and miR-605 accelerates the switching behavior of p53 levels to induce apoptosis. In parallel, miR-34a promotes apoptosis by enhancing the accumulation of free p53AIP1, a key proapoptotic protein. Thus, both miR-605 and miR-34a can mediate cellular outcomes and the timing of apoptosis. Moreover, miR-605 and PTEN complement each other in elevating p53 levels to trigger apoptosis. Taken together, miR-605 and miR-34a cooperate to endow the network with a fail-safe mechanism for apoptosis induction. This computational study also enriches our understanding of the action modes of p53-targeted microRNAs.