The Human T-Cell Leukemia Virus Type 1 Basic Leucine Zipper Factor Attenuates Repair of Double-Stranded DNA Breaks via Nonhomologous End Joining
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 tha...Continue Reading
References
A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination
Homologous recombination as a mechanism for genome rearrangements: environmental and genetic effects
Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation
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