Nucleic Acids Research Advance Access published online on September 18, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp745
Genome Integrity, Repair and Replication |
Influence of local sequence context on damaged base conformation in human DNA polymerase 
: molecular dynamics studies of nucleotide incorporation opposite a benzo[a]pyrene-derived adenine lesion
Department of Biology, New York University, New York, NY 10003, USA
*To whom correspondence should be addressed. Tel: +1 212 998 8231; Fax: +1 212 995 4015; Email: broyde{at}nyu.edu
Received July 6, 2009. Revised August 24, 2009. Accepted August 24, 2009.
Human DNA polymerase 
is a lesion bypass polymerase of the Y family, capable of incorporating nucleotides opposite a variety of lesions in both near error-free and error-prone bypass. With undamaged templating purines polymerase normally favors Hoogsteen base pairing. Polymerase can incorporate nucleotides opposite a benzo[a]pyrene-derived adenine lesion (dA*); while mainly error-free, the identity of misincorporated bases is influenced by local sequence context. We performed molecular modeling and molecular dynamics simulations to elucidate the structural basis for lesion bypass. Our results suggest that hydrogen bonds between the benzo[a]pyrenyl moiety and nearby bases limit the movement of the templating base to maintain the anti glycosidic bond conformation in the binary complex in a 5'-CAGA*TT-3' sequence. This facilitates correct incorporation of dT via a Watson–Crick pair. In a 5'-TTTA*GA-3' sequence the lesion does not form these hydrogen bonds, permitting dA* to rotate around the glycosidic bond to syn and incorporate dT via a Hoogsteen pair. With syn dA*, there is also an opportunity for increased misincorporation of dGTP. These results expand our understanding of the versatility and flexibility of polymerase and its lesion bypass functions in humans.