HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

Abstract

Transient HTLV-1 Tax expression suppresses cellular nucleotide excision repair, and this e ect correlates with Tax transactivation of the proliferating cell nuclear antigen promoter. The inability to repair DNA damage typically induces apoptotic cell death. Therefore, we investigated the e ect of Tax-mediated suppression of DNA repair on apoptosis in stable Tax-expressing cells. Constitutive Tax expression reduced cellular nucleotide excision repair activity compared with parental and control cells. Tax-expressing cells were also more sensitive to apoptosis induced by DNA damaging agents than control cells. Even though Tax-expressing cells displayed reduced DNA repair, they showed increased DNA replication following UV damage. These results suggest that Tax suppresses the cell's ability to repair DNA damage and stimulates DNA replication even in the presence of damage. The inability to repair DNA damage is likely to stimulate apoptotic cell death in the majority of Tax-expressing cells while the ability to promote DNA replication may also allow the survival of a small population of cells. We propose that together these e ects contribute to the monoclonal nature and low e ciency of HTLV-1 transformation.

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

“…HBV HBx represses DNA repair in p53-deficient cells and inhibits p53-dependent DNA repair (Prost et al, 1998;Groisman et al, 1999). Interestingly, Tax, HBx and LMP1 all sensitize cells to DNA damage (Capovilla et al, 1997;Kao et al, 2000a;Liu et al, 2004). Comparison of Tax, HBx and LMP1 shows that Tax and HBx are transactivators but LMP1 is a membrane protein.…”

Molecular mechanisms of cellular transformation by HTLV-1 Tax

“…Oncogenes such as Myc, E1A and E2F-1 all demonstrate such duality, and Tax may share this property. There is evidence that Tax protects cells from stress-induced cell cycle arrest or apoptosis (Copeland et al, 1994;Brauweiler et al, 1997;Torgeman et al, 2001;Kasai and Jeang, 2004), but can also sensitize cells to stress-induced apoptosis (Chlichlia et al, 1995(Chlichlia et al, , 1997(Chlichlia et al, , 2002Kao et al, 2000;Kasai and Jeang, 2004). This duality may be because transforming insults induce countervailing responses by the cell's tumor suppressors, which often manifest as cell cycle arrest and/or apoptosis.…”

Genomic instability driven by the human T-cell leukemia virus type I (HTLV-I) oncoprotein, Tax

“…Cells from patients with ATL display a variety of chromosomal abnormalities, such as duplications, deletions, translocations, and euploidy, suggesting that transformation by HTLV-I is associated with genomic instability (reviewed in Kao et al, 2000b). The viral oncoprotein Tax is essential for HTLV-I-mediated cellular transformation (Nerenberg et al, 1987;Pozzatti et al, 1990;Tanaka et al, 1990;Yamaoka et al, 1992).…”

“…Treatment with PALA is known to induce a p53-dependent G 1 cell cycle arrest, in response to unbalanced nucleotide pools (Linke et al, 1996), to prevent cells from undergoing DNA replication in the (Kao et al, 2000a) were treated with the indicated concentrations of N-(phosphonoacetyl)-L-aspartate (PALA) (Drug Synthesis and Chemistry Branch of the Division of Cancer Treatment at the National Cancer Institute, Bethesda, MD, USA). Seventy-two hours later, cells were stained with Trypan blue, and viable (i.e.…”

“…Cells isolated from ATL patients display a wide variety of chromosomal abnormalities, including deletions, duplications, translocations, and inversions (reviewed in Kao et al, 2000b), suggesting that HTLV-I affects genomic stability. Given that the HTLV-I viral oncoprotein, Tax, has been shown to be essential for HTLV-I mediated cellular transformation (Nerenberg et al, 1987;Pozzatti et al, 1990;Tanaka et al, 1990;Yamaoka et al, 1992), it is likely the viral protein responsible for the virally associated genomic instability observed in ATL cells.…”