The intracellular localization of APE1/Ref-1: more than a passive phenomenon?

Human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) is a perfect paradigm of the functional complexity of a biological macromolecule. First, it plays a crucial role, by both redox-dependent and -independent mechanisms, as a transcriptional coactivator for different transcription factors, either ubiquitous (i.e., AP-1, Egr-1, NF-kappaB, p53, HIF) or tissue-specific (i.e., PEBP-2, Pax-5 and -8, TTF-1), in controlling different cellular processes such as apoptosis, proliferation, and differentiation. Second, it acts, as an apurinic/apyrimidinic endonuclease, during the second step of the DNA base excision repair pathway, which is responsible for the repair of cellular alkylation and oxidative DNA damages. Third, it controls the intracellular reactive oxygen species production by negatively regulating the activity of the Ras-related GTPase Rac1. Despite these known functions of APE1/Ref-1, information is still scanty about the molecular mechanisms responsible for the coordinated control of its several activities. Some evidence suggests that the expression and subcellular localization of APE1/Ref-1 are finely tuned. APE1/Ref-1 is a ubiquitous protein, but its expression pattern differs according to the different cell types. APE1/Ref-1 subcellular localization is mainly nuclear, but cytoplasmic staining has also been reported, the latter being associated with mitochondria and/or presence within the endoplasmic reticulum. It is not by chance that both expression and subcellular localization are altered in several metabolic and proliferative disorders, such as in tumors and aging. Moreover, a fundamental role played by different posttranslational modifications in modulating APE1/Ref-1 functional activity is becoming evident. In the present review, we tried to put together a growing body of information concerning APE1/Ref-1's different functions, shedding new light on present and future directions to understand fully this unique molecule.