Susan Marriott, Ph.D.
Department of Molecular Virology and Microbiology
Ph.D.: Kansas State University, Manhattan
Postdoctoral training: National Institutes of Health, Bethesda
Cellular Transformation Mediated by Human Retroviruses
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. My laboratory uses Tax as a model system to understand cellular transformation. Our efforts are focused on:
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 attenuates the ability of ATM to establish DNA repair foci and 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.
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 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.
Baylor College of Medicine
One Baylor Plaza, 855E
Houston, TX 77030
- 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.
- 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.
- Johnson C, SJ Marriott and LS Levy. (2007). Overexpression of p101 activates PI3Kg signaling in T-cells and contributes to cell survival. Oncogene 26:7049-57.
- Winter HY and Marriott SJ. (2007). Human T cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J. Virol. 81:6089-6098.
- Gatza ML and Marriott SJ. (2006). Genotoxic stress alters the subcellular distribution of HTLV-1 Tax through a CRM1-dependent mechanism. J. Virol. 80:6657-6668.
- Marriott SJ and Semmes J. (2005). Impact of HTLV-I on the repair of cellular DNA-damage. Oncogene 24:5986-5995.
- Gatza ML, Chandhasin C, Ducu RI and Marriott SJ. (2005). Impact of transforming viruses on cellular mutagenesis, genome stability and cellular transformation. Environmental and Molecular Mutagenesis 45:1-7.
- Gatza M, Watt J and Marriott SJ. (2003). Cellular transformation by the HTLV-I Tax protein: a jack of all trades. Oncogene Reviews 22:5131-5140.
- Lemoine FJ and Marriott SJ. (2002). Genomic instability driven by the human T cell leukemia virus type I (HTLV-I) oncoprotein, Tax. Oncogene 21:7230-7234.
- Lemoine FJ and Marriott SJ. (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.