EAPII (also called TTRAP, TDP2) originally was identified as an interacting partner of oncogene ETS1, a founding member of ets transcription factor, and the cytoplasmic domain of CD40, a member of the tumor necrosis factor (TNF) receptor family. EAPII significantly represses ETS1 transcriptional activity and the synergistic transactivation by ETS1 and AP-1 or by ETS1 and NFκB. EAPII/TTRAP also inhibits the transcriptional activation of NFB induced by CD40 or phorbol 12-myristate 13-acetate (PMA). Recently this protein was also proven to be the first 5’- tyrosyl-DNA phosphodiesterase. EAPII has been demonstrated to have promiscuous protein associations, broad responsiveness to various extracellular signals, and pleiotropic functions in the development of human diseases including cancer and neurodegenerative disease. Emerging data suggest that EAPII is a multi-functional protein: it repairs enzyme (topoisomerase)-mediated DNA damage by removing phosphotyrosine from DNA adducts; involves in multiple signal transduction pathways such as TNF-TNFR, TGFβ and MAPK, and responsive to immune defense including inflammatory response, viral infection and DNA toxins (chemo or radiation therapy). EAPII predominantly localizes to the nucleus, but based on pathological conditions it also localizes in both cytoplasm and nucleus.