Suppression of DNA repair by human T cell leukemia virus type 1 Tax is rescued by a functional p53 signaling pathway.
The Tax protein of human T cell leukemia virus type 1 is a viral transactivator and transforming protein. Tax is known to suppress cellular nucleotide excision repair (NER), and this activity has been proposed to play an important role in Tax transformation. In this study we have investigated the mechanism by which Tax suppresses NER with specific focus on the previously characterized ability of Tax to inhibit p53 function. Suppression of NER by Tax was rescued by overexpression of wild-type p53; however, a p53 transactivation-incompetent mutant did not restore NER activity. The cyclin-dependent kinase inhibitor p21, a major transcriptional target of p53, plays an important role in regulating DNA replication and repair. Overexpression of p21 reversed Tax-induced suppression of NER; however, a p21 C-terminal mutant that lacks the proliferating cell nuclear antigen binding domain did not restore NER activity. Thus, p53 and its downstream effector p21 can inhibit Tax-mediated suppression of DNA repair. These results imply that the inactivation of p53 function by Tax contributes to Tax suppression of DNA repair.
Kao
S Y
SY
Department of Molecular Virology and Microbiology and Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Lemoine
F J
FJ
Marriott
S J
SJ
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004260:DNA Repair / Q000235:genetics*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1; D006801:Humans; D009154:Mutation / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D016356:Gene Products, tax; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)