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Vol. 59, Issue 2, 367-374, February 2001
Departments of Pharmaceutical Sciences (E.Y.K., N.F.K., A.E.G.,
W.E.E.) and Virology and Molecular Biology (K.G.M.), St. Jude
Children's Research Hospital, Memphis, Tennessee; and University of
Tennessee, Memphis, Tennessee (E.Y.K., N.F.K., W.E.E)
To elucidate molecular mechanism(s) of cellular response to
mercaptopurine, a widely used antileukemic agent, we assessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and
MMR deficient human acute lymphoblastic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e.,
MutS
) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear
extracts from ALL cells with synthetic 34-mer DNA duplexes containing
deoxythioguanosine (GS) within either GS·T or
GS·C pairs, resulted in formation of a DNA-protein
complex distinct from the DNA-MutS complex and unaffected by ATP.
Isolation and sequence analysis of proteins involved in this
DNA-protein complex identified glyceraldehyde 3-phosphate dehydrogenase
(GAPDH) as a component. Western blot analysis of nuclear extracts from
a panel of human lymphoblastic leukemia cell lines revealed markedly different basal levels of GAPDH in nuclei, which was significantly related to thiopurine sensitivity (p = 0.001).
Confocal analysis revealed markedly different intracellular
distribution of GAPDH between nucleus and cytosol in six human ALL cell
lines. Redistribution of GAPDH from cytosol to nucleus was evident
after MP treatment. These findings indicate that a new DNA-protein
complex containing GAPDH and distinct from known MMR protein-DNA
complexes binds directly to thioguanylated DNA, suggesting that this
may act as a sensor of structural alterations in DNA and serve as an
interface between these DNA modifications and apoptosis.
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