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Intrinsic DNA synthesis fidelity of xenotropic murine leukemia virus-related virus reverse transcriptase

AutorBarrioluengo, Verónica ; Wang, Yi; Le Grise, Stuart, F.J.; Menéndez-Arias, Luis
Palabras claveXMRV
Reverse transcriptase
DNA polymerase
Fecha de publicaciónabr-2012
EditorBlackwell Publishing
CitaciónFEBS Journal 279: 1433- 1444 (2012)
ResumenAlthough recent reports have provided strong evidence to suggest that xenotropic murine leukemia virus-related virus (XMRV) is unlikely to be the causative agent of prostate cancer and chronic fatigue syndrome, this recombinant retrovirus can nonetheless infect human cells in vitro and induce a chronic infection in macaques. In the present study, we determined the accuracy of DNA synthesis of the reverse transcriptases (RTs) of XMRV and Moloney murine leukemia virus (MoMLV) using a combination of pre-steady-state kinetics of nucleotide incorporation and an M13mp2-based forward mutation assay. The results obtained were compared with those previously reported for the HIV type 1 BH10 strain (HIV-1 BH10) RT. MoMLV and XMRV RTs were 13.9 and 110 times less efficient [as determined by the catalytic rate constant of the nucleotide incorporation reaction (k pol)/equilibrium constant (K d)] than the HIV-1 BH10 RT in incorporating correct nucleotides. Misinsertion and mispair extension kinetic studies demonstrated that MoMLV RT was more accurate than the HIV-1 BH10 RT. In comparison with the MoMLV RT, the XMRV RT showed decreased mispair extension fidelity and was less faithful when misincorporating C or A opposite A. However, the XMRV RT showed stronger selectivity against G in misinsertion fidelity assays. Forward mutation assays revealed that XMRV and MoMLV RTs had similar accuracy of DNA-dependent DNA synthesis, but were > 13 times more faithful than the HIV-1 BH10 enzyme. The mutational spectra of XMRV and MoMLV RTs were similar in having a relatively higher proportion of frameshifts and transversions compared with the HIV-1 BH10 RT. However, the XMRV polymerase was less prone to introduce large deletions and one-nucleotide insertions. © 2012 The Authors Journal compilation © 2012 FEBS.
Identificadoresdoi: 10.1111/j.1742-4658.2012.08532.x
issn: 1742-464X
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