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      The Human T-Cell Leukemia Virus Type 1 Basic Leucine Zipper Factor Attenuates Repair of Double-Stranded DNA Breaks via Nonhomologous End Joining

      , , ,
      Journal of Virology
      American Society for Microbiology

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          ABSTRACT

          Adult T-cell leukemia (ATL) is a fatal malignancy of CD4 + T cells infected with human T-cell leukemia virus type 1 (HTLV-1). ATL cells often exhibit random gross chromosomal rearrangements that are associated with the induction and improper repair of double-stranded DNA breaks (DSBs). The viral oncoprotein Tax has been reported to impair DSB repair but has not been shown to be consistently expressed throughout all phases of infection. The viral oncoprotein HTLV-1 basic leucine zipper (bZIP) factor (HBZ) is consistently expressed prior to and throughout disease progression, but it is unclear whether it also influences DSB repair. We report that HBZ attenuates DSB repair by nonhomologous end joining (NHEJ), in a manner dependent upon the bZIP domain. HBZ was found to interact with two vital members of the NHEJ core machinery, Ku70 and Ku80, and to be recruited to DSBs in a bZIP-dependent manner in vitro. We observed that HBZ expression also resulted in a bZIP-dependent delay in DNA protein kinase (DNA-PK) activation following treatment with etoposide. Although Tax is reported to interact with Ku70, we did not find Tax expression to interfere with HBZ:Ku complex formation. However, as Tax was reported to saturate NHEJ, we found that this effect masked the attenuation of NHEJ by HBZ. Overall, these data suggest that DSB repair mechanisms are impaired not only by Tax but also by HBZ and show that HBZ expression may significantly contribute to the accumulation of chromosomal abnormalities during HTLV-1-mediated oncogenesis.

          IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) infects 15 million to 20 million people worldwide. Approximately 90% of infected individuals are asymptomatic and may remain undiagnosed, increasing the risk that they will unknowingly transmit the virus. About 5% of the HTLV-1-positive population develop adult T-cell leukemia (ATL), a fatal disease that is not highly responsive to treatment. Although ATL development remains poorly understood, two viral proteins, Tax and HBZ, have been implicated in driving disease progression by manipulating host cell signaling and transcriptional pathways. Unlike Tax, HBZ expression is consistently observed in all infected individuals, making it important to elucidate the specific role of HBZ in disease progression. Here, we present evidence that HBZ could promote the accumulation of double-stranded DNA breaks (DSBs) through the attenuation of the nonhomologous end joining (NHEJ) repair pathway. This effect may lead to genome instability, ultimately contributing to the development of ATL.

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          Most cited references90

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          DNA double-strand breaks: signaling, repair and the cancer connection.

          To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation-the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.
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            XRCC3 promotes homology-directed repair of DNA damage in mammalian cells.

            Homology-directed repair of DNA damage has recently emerged as a major mechanism for the maintenance of genomic integrity in mammalian cells. The highly conserved strand transferase, Rad51, is expected to be critical for this process. XRCC3 possesses a limited sequence similarity to Rad51 and interacts with it. Using a novel fluorescence-based assay, we demonstrate here that error-free homology-directed repair of DNA double-strand breaks is decreased 25-fold in an XRCC3-deficient hamster cell line and can be restored to wild-type levels through XRCC3 expression. These results establish that XRCC3-mediated homologous recombination can reverse DNA damage that would otherwise be mutagenic or lethal.
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              Regulation of DNA repair throughout the cell cycle.

              The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for genome integrity. DNA lesions activate checkpoint pathways that regulate specific DNA-repair mechanisms in the different phases of the cell cycle. Checkpoint-arrested cells resume cell-cycle progression once damage has been repaired, whereas cells with unrepairable DNA lesions undergo permanent cell-cycle arrest or apoptosis. Recent studies have provided insights into the mechanisms that contribute to DNA repair in specific cell-cycle phases and have highlighted the mechanisms that ensure cell-cycle progression or arrest in normal and cancerous cells.
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                Author and article information

                Journal
                Journal of Virology
                J Virol
                American Society for Microbiology
                0022-538X
                1098-5514
                August 01 2018
                July 17 2018
                May 16 2018
                : 92
                : 15
                Article
                10.1128/JVI.00672-18
                6052317
                29769340
                6061dab1-ef6f-42d4-9a6d-0b394b44e0f0
                © 2018
                History

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