The HTLV-1 tax oncoprotein attenuates DNA damage induced G1 arrest and enhances apoptosis in p53 null cells.
Transformation of cells by the human T cell leukemia virus type 1 occurs via mechanisms unique among oncogenic retroviruses. A prevailing hypothesis for HTLV-1-mediated cellular transformation is that expression of the viral transactivator, Tax, induces genomic instability. Tax-mediated failure in the cellular repair response is one possible mechanism for loss in genomic integrity. Here we have examined the in vivo repair response of Tax-expressing cells to determine the underlying defects that contribute to loss of genomic integrity. In these studies we examined the effects of de novo Tax-expression in naive "pre-neoplastic" REF52 cells. DNA-damage-induced p53 stabilization and concomitant transient stabilization of p21 were clearly evident in Tax-expressing cells. Likewise, the damage-induced apoptotic response of Tax-expressing cells was normal. However, the damage-induced G1 checkpoint was abrogated in either p53+ or p53- cellular backgrounds. Although nucleotide excision repair (NER) of asynchronous Tax-expressing cells was impaired, cell-cycle-independent assessment of NER in the global excision repair assay demonstrated comparable NER activity in Tax-expressing cells, suggesting that the failure of G1 checkpoint contributes to NER deficiency. Interestingly, we observed a dramatic increase in apoptosis and UV sensitivity of Tax-expressing p53-/- cells when compared to Tax-expressing p53+/+ cells. These data demonstrate that Tax-mediated cellular genomic instability arises from attenuation of cell-cycle checkpoint and imply a clonal dependence on p53 status separate from genomic integrity.
Haoudi
Abdelali
A
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA.
Semmes
O John
OJ
D017209:Apoptosis; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair; D016193:G1 Phase / Q000502:physiology*; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016356:Gene Products, tax; D016159:Tumor Suppressor Protein p53