The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme β-polymerase

Objective: This study examines the effects of the HIV-1 regulatory proteins, Tat and Rev, on the expression of the DNA polymerase beta (beta -pol) gene, which encodes a key protein in the DNA base-excision repair pathway. The rationale for these experiments is to examine the potential involvement of base-excision repair protein deregulation in HIV-1-related lymphomas. Design: Expression of beta -pol mRNA was examined in AIDS-related lymphomas and non-AIDS-related lymphomas and as a function of HIV-1 infection of B cells in culture. The effect of Tat or Rev over-expression on beta -pol promoter expression was tested by transient co-transfection assays with a beta -pol promoter reporter plasmid and a Tar or Rev over-expression plasmid. Methods: Northern blot analysis was used to quantitate beta -pol expression in lymphoma and cells. Raji cells were co-transfected with a chloramphenicol acetyltransferase (CAT) reporter plasmid and a plasmid over-expressing Tat or Rev. CAT activity was measured in transfected cells. Results: beta -Pol mRNA was >10-fold higher in AIDS-related than in non-AIDS B-lineage lymphomas. beta -Pol expression was up-regulated in a B-cell line upon infection with HIV-1, and increased in Raji cells upon recombinant expression of the Tar gene. The beta -pol promoter was transactivated (fourfold induction) by Tat, but not by Rev. Tat-dependent transactivation required a binding site for the transcription factor Sp1 in the beta -pol promoter. Conclusion: These results suggest that HIV-1 Tat can interact with cellular transcription factors to increase the steady-state level of beta -pol in B cells. Tat-mediated induction of beta -pol may alter DNA stability in AIDS-related lymphomas. (C) 2001 Lippincott Williams & Wilkins.