Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive clonal malignancy of CD4+ T cells. HTLV-I encodes a regulatory protein, Tax, which is responsible for the transforming potential of HTLV-I. Although the precise mechanism remains unknown, Tax transformation depends upon its ability to activate cellular growth regulatory genes, and to modulate cellular signaling pathways. We have recently demonstrated that Tax stimulates cell cycle progression through G1 phase, suppresses DNA repair, and interferes with the DNA damage-induced G1/S checkpoint. These functions allow Tax-expressing cells to enter S phase and initiate DNA replication prior to the completion of DNA repair, creating an environment that promotes the fixation of DNA mutations into the host genome. Transformed lymphocytes isolated from ATL patients as well as Tax expressing cell lines display a variety of genomic abnormalities that are consistent with this activity. Together, these observations provide an intriguing model for Tax-mediated transformation, which will be further investigated through this renewal application. The overall hypothesis for these studies is that Tax-expressing cells fail to maintain the G1/S DNA damage induced checkpoint, thereby increasing the cellular mutation frequency and enhancing the potential for cellular transformation.
The specific aims of this application are: (1) To determine the mechanism by which Tax allows bypass of the G1/S DNA damage induced cell cycle checkpoint. (2) To determine the consequences of S phase entry in the presence of DNA damage. (3) To determine the effect of Tax on mutation frequency and cellular transformation. The results of these studies will define critical steps in the specific process of HTLV-I transformation and are likely to provide broader insights into mechanisms of cellular proliferation and transformation.
|Dayaram, Tajhal; Lemoine, Francene J; Donehower, Lawrence A et al. (2013) Activation of WIP1 phosphatase by HTLV-1 Tax mitigates the cellular response to DNA damage. PLoS One 8:e55989|
|Ducu, Razvan I; Dayaram, Tajhal; Marriott, Susan J (2011) The HTLV-1 Tax oncoprotein represses Ku80 gene expression. Virology 416:1-8|
|Guimaraes-Correa, Ana B; Crawford, Lindsey B; Figueiredo, Carlos R et al. (2011) C7a, a biphosphinic cyclopalladated compound, efficiently controls the development of a patient-derived xenograft model of adult T cell leukemia/lymphoma. Viruses 3:1041-58|
|Dayaram, Tajhal; Marriott, Susan J (2008) Effect of transforming viruses on molecular mechanisms associated with cancer. J Cell Physiol 216:309-14|
|Edwards, Dustin C; Marriott, Susan J (2008) Human T-cell leukemia virus type 1 Tax relieves repression of proliferating cell nuclear antigen gene expression. J Virol 82:11714-22|
|Chandhasin, Chandtip; Ducu, Razvan I; Berkovich, Elijahu et al. (2008) Human T-cell leukemia virus type 1 tax attenuates the ATM-mediated cellular DNA damage response. J Virol 82:6952-61|
|Gatza, Michael L; Dayaram, Tajhal; Marriott, Susan J (2007) Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export. Retrovirology 4:95|
|Winter, Heather Y; Dayaram, Tajhal; Marriott, Susan J (2007) Activation of the human T-cell leukemia virus type 1 long terminal repeat by the ternary complex factor Elk-1. J Virol 81:13075-81|
|Winter, Heather Y; Marriott, Susan J (2007) Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J Virol 81:6089-98|
|Gatza, Michael L; Marriott, Susan J (2006) Genotoxic stress and cellular stress alter the subcellular distribution of human T-cell leukemia virus type 1 tax through a CRM1-dependent mechanism. J Virol 80:6657-68|
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