Mitochondria-nucleus communications and DNA damage response (DDR) play roles in cellular stress and closely associate with a range of diseases. Mitochondrial uncoupling proteins (UCPs) are capable of uncoupling mitochondrial oxidative phosphorylation and protecting against oxidative stress. However, the potential role of UCPs in DDR and DDR-related mitochondria-nucleus communications remains unknown. The review deduces UCPs functions in mitochondria-nucleus communications implicated in metabolite regulation (e.g., reactive oxygen species) and Ca2+ signaling, and in DDR (e.g., base excision repair, double-strand DNA break repair, mitophagy and nuclear DNA degradation). Represented are shared microRNAs that regulate UCPs and DDR. It would provide novel insight into UCPs-mediated mitochondria-nucleus communications and DDR, and potentially promote drug target identification, drug discovery and clinical therapy of DDR-related diseases.