Research Perspective Volume 3, Issue 5 pp 543—547

Figure 1. Linking DNA damage to mitochondrial biogenesis. Upon DNA damage, PARP activity in the cell is highly enhanced. The activation PARP-1, the enzyme responsible for most PARP activity, would lead to NAD⁺ depletion, therefore limiting SIRT1 activity by lowering the bioavailability of this crucial coenzyme. PARP-2 binds to the SIRT1 promoter, inhibiting transcription, resulting in reduced SIRT1 levels. In all, both enzymes would co-ordinately lead to a decrease in SIRT1 activity through different means. The reduction in SIRT1 activity would reduce the deacetylation rate of several transcriptional regulators, such as PGC-1a. The resulting hyperacetylation of PGC-1a would then decrease mitochondrial-related gene expression, having a strong impact on metabolic disease and, potentially, a healthy ageing.