HTLV-I Tax Promotes Genomic Instability by Interfering with Repair of DNA Breaks (pp. 125-144)
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Authors: (Razvan I. Ducu, Susan J. Marriott, Department of Molecular Virology and Microbiology, Houston, USA)
Abstract: An emerging mechanism of cellular transformation by oncogenic viruses is the
inhibition or suppression of cellular DNA repair. This review will focus on human T-cell
leukemia virus (HTLV-I), which is the causative agent of adult T-cell leukemia (ATL),
an aggressive clonal malignancy of CD4+ T lymphocytes. The oncogenic potential of
HTLV-I relies on expression of the viral transcriptional modulator, Tax. In addition to
activating viral transcription, Tax controls the expression of a large and diverse array of
cellular genes. By altering gene expression homeostasis, as well as by direct proteinprotein
interactions, Tax interferes with normal DNA replication and repair processes,
thereby contributing to an increased mutation frequency in HTLV-I infected cells. We
and others have shown that Tax can suppress DNA base and nucleotide excision repair
pathways by altering the expression of important factors involved in these pathways,
such as DNA polymerase beta and PCNA. Tax has also been shown to affect protein
interactions that regulate DNA repair pathways and to attenuate the ATM mediated
damage response, a major pathway for repair of DNA double strand breaks (DSBs). In
this chapter we will review the effect of Tax on DNA repair and genome stability and the
role of these processes in cellular transformation. We will discuss the inhibitory effect of
Tax on ATM kinase activity, which reveals novel insights into the normal function of
this signaling and repair pathway. Finally, we will discuss recent data suggesting a
critical role for the DNA double strand break repair pathway in retroviral replication and
tumor suppression.
