Dk. Srivastava et al., The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase, AIDS, 15(4), 2001, pp. 433-440
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) gen
e, 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 c
ells in culture. The effect of Tat or Rev over-expression on beta -pol prom
oter 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 chloramphenic
ol acetyltransferase (CAT) reporter plasmid and a plasmid over-expressing T
at or Rev. CAT activity was measured in transfected cells.
Results: beta -Pol mRNA was >10-fold higher in AIDS-related than in non-AID
S B-lineage lymphomas. beta -Pol expression was up-regulated in a B-cell li
ne upon infection with HIV-1, and increased in Raji cells upon recombinant
expression of the Tar gene. The beta -pol promoter was transactivated (four
fold induction) by Tat, but not by Rev. Tat-dependent transactivation requi
red a binding site for the transcription factor Sp1 in the beta -pol promot
er.
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.