The anticancer activity of cytarabine (AraC) and gemcitabine (dFdC) is thought
to result from chain termination after incorporation into DNA. To investigate
their incorporation into DNA at atomic level resolution, we present crystal
structures of human DNA polymerase lambda (Pol lambda) bound to gapped DNA and
containing either AraC or dFdC paired opposite template dG. These structures
reveal that AraC and dFdC can bind within the nascent base pair binding pocket
of Pol lambda. Although the conformation of the ribose of AraCTP is similar to
that of normal dCTP, the conformation of dFdCTP is significantly different.
Consistent with these structures, Pol lambda efficiently incorporates AraCTP but
not dFdCTP. The data are consistent with the possibility that Pol lambda could
modulate the cytotoxic effect of AraC.
