HTLV-I tax increases genetic instability by inducing DNA double strand breaks during DNA replication and switching repair to NHEJ.
BACKGROUND
Appropriate responses to damaged DNA are indispensible for preserving genome stability and preventing cancer. Tumor viruses often target DNA repair machinery to achieve transformation. The Human T-cell leukemia virus type I (HTLV-I) is the only known transforming human retrovirus and the etiological agent of Adult T-cell Leukemia (ATLL). Although HTLV-I-transformed leukemic cells have numerous genetic lesions, the precise role of the viral tax gene in this process is not fully understood.


RESULTS
Our results show a novel function of HTLV-I oncoprotein Tax as an inducer of genomic DNA double strand breaks (DDSB) during DNA replication. We also found that Tax acts as a potent inhibitor of homologous recombination (HR) DNA repair through the activation of the NF-kB pathway. These results were confirmed using HTLV-I molecular clones expressing Tax at physiological levels in a natural context. We further found that HTLV-I- and Tax-transformed cells are not more susceptible to DNA damaging agents and repair DNA lesions at a rate similar to that of normal cells. Finally, we demonstrated that during S phase, Tax-associated DDSB are preferentially repaired using the error-prone non-homologous end joining (NHEJ) pathway.


CONCLUSIONS
This study provides new insights in Tax effects on DNA repair and genome instability. Although it may not be self sufficient, the creation of DNA breaks and subsequent abnormal use of the non-conservative NHEJ DNA repair during the S phase in HTLV-I-infected Tax-expressing cells may cooperate with other factors to increase genetic and genome instability and favor transformation.
University of Kansas Medical Center, Department of Pathology and Laboratory Medicine, Kansas City, Kansas, USA.
Hicham H
HH
Baydoun
Xue Tao
XT
Bai
Shary
S
Shelton
Christophe
C
Nicot
D015153:Blotting, Western; D002460:Cell Line; D020552:Comet Assay; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004261:DNA Replication; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism
D016356:Gene Products, tax; D016328:NF-kappa B; C514970:tax protein, Human T-lymphotrophic virus 1