DNA Damage-induced Post-transcriptional Regulation of SIRT4 by the miR-15/16 Family Modulates Chemosensitivity in Cancer Cells

BACKGROUND/AIM: SIRT4 is a mitochondrial regulator of metabolism and stress responses, yet the mechanisms underlying its induction upon DNA damage remains unclear. This study aimed to define the mechanism of SIRT4 regulation and the role of the miR-15/16 family in this process. MATERIALS AND METHODS: SIRT4 expression was examined after DNA-damaging treatments in MEFs and HeLa cells. Reporter assays, mRNA decay analysis, and mutagenesis of the SIRT4 3'UTR were performed to identify regulatory mechanisms. Gain- and loss-of-function studies assessed the involvement of the miR-15/16 family. Cell viability was evaluated. RESULTS: SIRT4 was strongly induced by DNA damage and required for cell survival under genotoxic stress. This induction occurred through mRNA stabilization with the 3'UTR of SIRT4 serving as the determinant of stability. The miR-15/16 family targeted a conserved site within the SIRT4 3'UTR to destabilize its mRNA. Overexpression of miR-15/16 reduced SIRT4 expression and sensitized cells to chemotherapy. CONCLUSION: The miR-15/16-SIRT4 axis represents a novel mechanism of post-transcriptional regulation in the DNA damage response and may serve as a therapeutic target to improve the efficacy of chemotherapy.