Genomic instability, a hallmark of leukemic cells, is associated with malfunctioning cellular responses to DNA damage caused by defective cell cycle checkpoints and/or DNA repair. Adult T-cell leukemia, which can result from infection with human T-cell leukemia virus type 1 (HTLV-1), is associated with extensive genomic instability that has been attributed to the viral oncoprotein Tax. How Tax influences cellular responses to DNA damage to mediate genomic instability, however, remains unclear. Therefore, we investigated the effect of Tax on cellular pathways involved in recognition and repair of DNA double-strand breaks. Premature attenuation of ATM kinase activity and reduced association of MDC1 with repair foci were observed in Tax-expressing cells. Following ionizing radiation-induced S-phase checkpoint activation, Tax-expressing cells progressed more rapidly than non-Tax-expressing cells toward DNA replication. These results demonstrate that Tax expression may allow premature DNA replication in the presence of genomic lesions. Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation.Preserving genomic integrity is critical for all living systems. The integrity and survival of a cell depend on the stability of its DNA. Damaged DNA is detected by cellular sensing systems, which activate specific DNA repair pathways. Malfunction of this repair network, collectively known as the DNA damage response, leads to DNA mutations, a subset of which can promote cellular transformation. Double-stranded DNA breaks (DSBs) arise from genotoxic insults and normal physiological processes such as DNA replication (24, 38). The mechanisms by which eukaryotic cells sense DNA breaks remain to be elucidated, but one of the earliest detectable events in DNA damage sensing is the activation of the ataxia telangiectasia mutated (ATM) kinase (45).ATM is a member of the PI3K-like kinase family and is mutated in ataxia telangiectasia patients (45). Immediately after exposure of cells to DSB-inducing agents such as ionizing radiation (IR) and radiomimetic drugs, changes in chromatin structure activate the intermolecular autophosphorylation of ATM on Ser1981, resulting in the dissociation of inactive ATM dimers into active monomers that allow substrate accessibility to the ATM kinase domain (2). ATM substrates include cellular targets such as NBS1, Chk2, p53, MDC1, histone 2AX (H2AX), and BRCA1, which are key players in the maintenance of genomic integrity (5,19,44,47). Some of these substrates are phosphorylated by ATM in the nucleoplasm, while others are phosphorylated at sites of DNA damage where ATM is recruited via interaction with the Mre11/Rad50/NBS1 (MRN) complex. At sites of DNA breaks within chromatin, the phosphorylation of H2AX and MDC1 by ATM establishes a positive-feedback loop that maintains ATM autophosphorylation and amplifies the DNA damage response (31). Genetic defects in crucial parts of this network lead to a grou...

It is estimated that 15% of all cancers are etiologically linked to viral infection. Specific cancers including adult T-cell leukemia, hepatocellular carcinoma, and uterine cervical cancer are associated with infection by human T-cell leukemia virus type I, hepatitis B virus, and high-risk human papilloma virus, respectively. In these cancers, genomic instability, a hallmark of multistep cancers, has been explicitly linked to the expression of oncoproteins encoded by these viruses. This review discusses mechanisms utilized by these viral oncoproteins, Tax, HBx, and E6/E7, to mediate genomic instability and cellular transformation.

The HTLV-I oncoprotein Tax interferes with DNA double strand break repair. Since non-homologous end joining (NHEJ) is a major pathway used to repair DNA double strand breaks we examined the effect of Tax on this pathway, with particular interest in the expression and function of Ku80, a critical component of the NHEJ pathway. Tax expression decreased Ku80 mRNA and protein levels, and repressed transcription from the Ku80 promoter. Conversely, Ku80 mRNA increased following siRNA knockdown of Tax in HTLV-I infected cells. Tax expression was associated with an elevated number of micronuclei and nucleoplasmic bridges, hallmarks of improper DNA double strand break repair. Our studies identified Tax as a transcriptional repressor of Ku80 that correlates with decreased DNA repair function. The reduction of Ku80 transcription by Tax may deplete the cell of an essential DNA break binding protein, resulting in reduced repair of DNA double strand breaks and accumulation genomic mutations.