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.
|Ho, Yik-Khuan; Zhi, Huijun; Bowlin, Tara et al. (2015) HTLV-1 Tax Stimulates Ubiquitin E3 Ligase, Ring Finger Protein 8, to Assemble Lysine 63-Linked Polyubiquitin Chains for TAK1 and IKK Activation. PLoS Pathog 11:e1005102|
|Ducroux, Aurélie; Benhenda, Shirine; Rivière, Lise et al. (2014) The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B Virus and herpes simplex virus type 1. PLoS Pathog 10:e1004343|
|Shulak, Laura; Beljanski, Vladimir; Chiang, Cindy et al. (2014) Histone deacetylase inhibitors potentiate vesicular stomatitis virus oncolysis in prostate cancer cells by modulating NF-?B-dependent autophagy. J Virol 88:2927-40|
|Welbourn, Sarah; Dutta, Sucharita M; Semmes, O John et al. (2013) Restriction of virus infection but not catalytic dNTPase activity is regulated by phosphorylation of SAMHD1. J Virol 87:11516-24|
|Benhenda, Shirine; Ducroux, Aurélie; Rivière, Lise et al. (2013) Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription. J Virol 87:4360-71|
|Lee, Song Hee; Kalejta, Robert F; Kerry, Julie et al. (2012) BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection. Proc Natl Acad Sci U S A 109:9575-80|
|Fryrear, Kimberly A; Guo, Xin; Kerscher, Oliver et al. (2012) The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax. Blood 119:1173-81|
|Williams, Stacy A; Wilson, James B; Clark, Allison P et al. (2011) Functional and physical interaction between the mismatch repair and FA-BRCA pathways. Hum Mol Genet 20:4395-410|
|Yeh, Pei-Chun; Han, Jun; Chadha, Pooja et al. (2011) Direct and specific binding of the UL16 tegument protein of herpes simplex virus to the cytoplasmic tail of glycoprotein E. J Virol 85:9425-36|
|Belgnaoui, S Mehdi; Fryrear, Kimberly A; Nyalwidhe, Julius O et al. (2010) The viral oncoprotein tax sequesters DNA damage response factors by tethering MDC1 to chromatin. J Biol Chem 285:32897-905|
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