This work investigates the role of the atypical dual tyrosine phosphatase 3 (DUSP3 or VHR) in Ionising Radiation Induced Foci (IRIF) in HeLa cells following gamma and ultraviolet C radiation. The goal is to identify possible involvements of this enzyme in DNA repair and genomic instability. Experimental approaches were based on: (a) fluorescence confocal microscopy of VHR and other proteins for determination of their expression and intracellular localisation, and (b) systems biology investigation of structural features of proteins known to be involved in DNA damage response and repair and comparison with known VHR substrates. At the IRIFs, VHR co-localises with p-H2AX and p-ATF2 after γ-ray, and with p-JNK and p-ATF2 after UVC radiation. Homology search approaches raised a list of several putative substrates for VHR based on sequence alignments. For some of these putative substrates the interaction was confocal microscopy analysis and shown to co-localised directly or indirectly (Mre11) with VHR in the IRIFs. These results shed light in the dual tyrosine phosphatases as players in DNA damage and response.