Human T-cell Leukemia Virus type 1 (HTLV-1) causes Adult T-cell Leukemia (ATL). Although the precise mechanism is unknown, cellular transformation is dependent upon expression of the viral protein Tax. We and others have shown that expression of Tax results in genomic instability and we hypothesize that loss of genomic integrity facilitates HTLV-1-mediated leukemogenesis. The objective of this application is to uncover the mechanism by which Tax disrupts normal cellular DNA damage response (DDR) and thus results in loss of genomic integrity. We hypothesize that Tax forms a damage- independent DDR complex that competitively inhibits normal cellular DDR. The impaired DDR contributes to genomic instability and thus we present a model for development of ATL. Our hypothesis is based upon our published findings and preliminary data establishing that Tax can recruit DDR proteins to nuclear foci that do not colocalize with sites of DNA damage. We show that Tax binds to MDC1 and recruits this DDR protein to damage-independent foci that we have previously identified as Tax Speckled Structures (TSS). Since it has been recently shown that artificial tethering of MDC1 to DNA is sufficient to initiate DDR, we propose that Tax initiates damage-independent DDR by recruiting proteins like MDC1. Our hypothesis will be tested in three specific aims. 1) Identification of DDR Proteins that Drive Competition between TSS and DNA Damage Induced Nuclear Foci. 2) Structural Characterization of TSS and Features of Tax that Drive TSS Formation. 3) Determine the Functional Significance of Competition for Recruitment of DDR Complexes to TSS. Successful completion of these studies will help define a novel virus-cell interaction strategy and provide for a better understanding of DDR and cellular transformation.
We propose that HTLV-1 Tax induces genomic instability by sequestration of DDR proteins into nuclear foci and competing with the cellular DNA damage recognition-repair response. This process results in cellular transformation and development of Adult T- Cell Leukemia. Uncovering the mechanism by which the viral oncogenic protein Tax competes with cellular DDR will help clarify HTLV-1 virus-host relationship and provide for a greater insight into the mechanics of cellular DDR. Understanding how oncoviruses control DDR will provide approaches for novel anti-cancer therapeutic strategies.
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