SIRT1 gene expression upon genotoxic damage is regulated by APE1 through nCaRE-promoter elements.

The Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein contributing to genome stability, through the repair of DNA lesions via BER pathway, also playing a role in gene expression regulation and in RNA metabolism. Another poorly characterized function is its ability to bind to negative calcium responsive elements (nCaRE) of some gene promoters. The occurrence of many functional nCaRE sequences, regulating gene transcription, could be envisioned since their conservation within ALU repeats. To look for functional nCaRE sequences within the human genome, we performed bioinformatic analyses and identified a list of 57 genes potentially regulated by APE1. We focused on the SIRT1 deacetylase due to its involvement in cell stress, including senescence, apoptosis and tumorigenesis, and its role in the deacetylation of APE1 after genotoxic stress. The human SIRT1 promoter presents two nCaRE elements stably bound by APE1 through its N-terminus. We demonstrate that APE1 is part of a multi-protein complex including hOGG1, Ku70 and RNA Pol II, which is recruited on SIRT1 promoter to regulate SIRT1 gene functions during early response to oxidative stress. These findings provide new insights in the comprehension of the role of nCaRE sequences in the transcriptional regulation of mammalian genes.