Fumarase: a paradigm of dual targeting and dual localized functions

The enzyme fumarase is a conserved protein in all organisms with regard to its sequence, structure and function. This enzyme participates in the tricarboxylic acid cycle in mitochondria which is essential for cellular respiration in eukaryotes. However, a common theme conserved from yeast to humans is the existence of a cytosolic form of fumarase; hence this protein is dual localized. We have coined identical (or nearly identical) proteins situated in different subcellular locations echoforms or echoproteins. Fumarase was the first example of a dual localized protein whose mechanism of distribution was found to be based on a single translation product. Consequently, fumarase has become a paradigm for three unique eukaryotic cellular phenomena related to protein dual localization: (a) distribution between mitochondria and the cytoplasm involves reverse translocation; (b) targeting to mitochondria involves translation coupled import; and (c) there are two echoforms possessing distinct functions in the respective subcellular compartments. Here we describe and discuss these fumarase related phenomena and in addition point out approaches for studying dual function of distributed proteins, in particular compartment-specific depletion. In the case of fumarase, the cytoplasmic function was only recently discovered; the enzyme was found to participate in the cellular response to DNA double strand breaks. Strikingly, upon DNA damage the protein is transported from the cytosol to the nucleus, where by virtue of its enzymatic activity it participates in the DNA damage response.