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Influence of local sequence context on damaged base conformation in human DNA polymerase ι: molecular dynamics studies of nucleotide incorporation opposite a benzo[a]pyrene-derived adenine lesion

Author:
Donny-Clark, Kerry, Broyde, Suse
Source:
Nucleic acids research 2009 v.37 no.21 pp. 7095-7109
ISSN:
0305-1048
Subject:
DNA-directed DNA polymerase, adenine, glycosidic linkages, humans, hydrogen bonding, molecular dynamics, molecular models, nucleic acids, nucleotides
Abstract:
Human DNA polymerase ι 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 ι normally favors Hoogsteen base pairing. Polymerase ι 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 ι and its lesion bypass functions in humans.
Agid:
2213495