Physical and in silico approaches identify DNA-PK in a Tax DNA-damage response interactome

We first constructed an in silico Tax interactome comprised of 46 literature-confirmed protein-protein interactions. This number was then reduced to four Tax-interactions suspected to play a role in DNA damage response (Rad51, TOP1, Chk2, 53BP1). The first-neighbor and second-neighbor interactions of these four proteins were assembled from available human protein interaction databases. Through an analysis of betweenness and closeness centrality measures, and numbers of interactions, we ranked proteins in the first neighborhood. When this rank list was compared to the list of physical Tax-binding proteins, DNA-PK was the highest ranked protein common to both lists. An overlapping clustering of the Tax-specific second-neighborhood protein network showed DNA-PK to be one of three bridge proteins that link multiple clusters in the DNA damage response network.The interaction of Tax with DNA-PK represents an important biological paradigm as suggested via consensus findings in vivo and in silico. We present this methodology as an approach to discovery and as a means of validating components of a consensus Tax interactome.Human T-cell Leukemia Virus type 1(HTLV-1) is the causative agent of Adult T-cell Leukemia (ATL), HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) as well as other subneoplastic conditions [1-5]. Although the development of ATL is the culmination of complex events, it appears that the viral oncogene product, Tax, may provide the impetus for the transformation process. This protein has been studied extensively since 1982 when Tax was discovered to be a transactivator of the cognate viral promoter [6]. Since that time many activities and subsequent functions have been assigned to the Tax protein [7-9]. The critical importance of this protein to human disease makes it a fascinating protein as a research target; however, the result of such focused research efforts has been thousands of articles and a healthy dose of controversy. These qualit