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Human T-cell leukemia virus (HTLV-I) is the etiologic agent of at least two human diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM). The viral genome encodes a regulatory protein, Tax, which functions as a transcriptional transactivator of viral and cellular gene expression, and is the transforming protein of HTLV-I. The primary interest of my laboratory is to use Tax as a model system to understand cellular transformation. Our efforts are focused on:

Defining the mechanism of Tax transactivation of the HTLV-I promoter located in the long terminal repeat (LTR). Tax does not bind DNA directly; however, it can associate with the cellular transcription factors including CREB, NF-kB, and SRF. We are investigating the molecular mechanisms of Tax transactivation of viral and cellular promoters with specific interest in the effect of Tax on chromatin remodeling through recruitment of histone acetyltransferases.
Determining the effect of Tax on cell cycle progression and DNA replication/repair. The ability of Tax to transform cells is thought to depend on its ability to activate expression of a select group of cellular genes. Tax activates transcription of the proliferating cell nuclear antigen (PCNA) promoter. PCNA is an essential co-factor of DNA polymerase delta and thus is intimately linked to DNA replication and repair. We have demonstrated that Tax can inhibit the cell’s ability to repair DNA damage. In cells expressing Tax, we propose that PCNA overexpression inhibits DNA repair and stimulates DNA replication, thus fixing mutations in the genome. Supporting this model, Tax stimulates cell cycle progression even in the presence of DNA damage. We have mapped this cell cycle defect to the G1/S checkpoint. The disruption of cellular mechanisms that coordinate DNA replication and repair may allow accumulation of DNA damage and thus play an important role in transformation.

Recent Publications (PubMed)

Chandhasin C, R Ducu, E Berkovich, MB Kastan and SJ Marriott. 2008. HTLV-I Tax attenuates the ATM-mediated DNA damage response. J. Virol (in press).

Winter HY and SJ Marriott. 2007. Human T cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J. Virol. 81:6089-6098.

Winter HY, Dayaram T, and SJ Marriott. 2007. Activation of the HTLV-I LTR by the ternary complex factor, Elk-1. J Virol 81:13075-13081. Gatza ML and SJ Marriott. 2007. Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export. Retrovirology 4:95.

Kwok RPS, ME Laurance, JR Lundblad, PS Goldman, H-M Shih, LM Connor, SJ Marriott, R Goodman. 1996. Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature 380:642-646.    

Ressler S, GF Morris and SJ Marriott. 1997. Human T-cell leukemia virus type-1 Tax transactivates the proliferating cell nuclear antigen promoter. J Virol 71:1181-1190.     

Kao S-Y and SJ Marriott. 1999. Disruption of nucleotide excision repair by the human T cell leukemia virus type-I Tax protein. J Virol 73:4299-4304.

Kao S-Y and SJ Marriott. 2000. Suppression of DNA repair by HTLV-I Tax is rescued by a functional p53 signaling pathway. J Biol Chem 275:35926-35931.

Lemoine FJ, and SJ Marriott. 2001. Accelerated G1 phase progression induced by the human T cell leukemia virus type I (HTLV-I) Tax oncoprotein. J Biol Chem 276:31851-31857.

Lemoine FJ and SJ Marriott. 2002. Genomic instability driven by the human T cell leukemia virus type I (HTLV-I) oncoprotein, Tax. Oncogene 21:7230-7234.

Gatza M., J. Watt and SJ Marriott. 2003.  Cellular transformation by the HTLV-I Tax protein: a jack of all trades. Oncogene Reviews 22:5131-5140.

Gatza ML, C Chandhasin, RI Ducu and SJ Marriott.  2005. Impact of transforming viruses on cellular mutagenesis, genome stability and cellular transformation. Environmental and Molecular Mutagenesis 45:1-7.

SJ Marriott and J Semmes.  2005. Impact of HTLV-I on the repair of cellular DNA-damage.  Oncogene 24:5986-5995.

Cavanagh M-H, S Landry, B Audet, C Arpin-André, P Hivin, M-È Paré, J Thête, É Wattel, SJ Marriott, MJ Tremblay, J-M Mesnard and B Barbeau.  2006. HTLV-I antisense transcripts initiate in the 3’LTR and are alternatively spliced and polyadenylated. Retrovirology 3:1742-4690.

Gatza ML and SJ Marriott. 2006. Genotoxic stress alters the subcellular distribution of HTLV-1 Tax through a CRM1-dependent mechanism. J. Virol. 80:6657-6668.