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

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.

Structural and energetic characterization of the major DNA adduct formed from the food mutagen ochratoxin A in the NarI hotspot sequence: influence of adduct ionization on the conformational preferences and implications for the NER propensity

“…If the adducts persist in cells, such mutations may ultimately lead to cancer, especially when the lesion is located at the (proto) oncogene or tumor suppressor gene. Therefore, a number of studies have been devoted to understanding the effects of adduct formation on cellular DNA processing ( 36 – 38 ). However, in order to understand these effects, the conformational preferences of the damaged DNA duplex must be first understood ( 39 ).…”

Base damage, local sequence context andTP53mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability

“…Selection dictates whether the mutation will be observed and the strength of selection can influence the shape of the mutation spectrum for TP53 in a given cancer. Sequence context influences both the rate of mutagen binding and the rate of lesion repair of adducts including those for BPDE by nucleotide excision repair (NER) ( 16 – 18 ). Binding affinity of BPDE with guanines at TP53 mutation hotspot CpG sites has been confirmed at codons 157, 158, 245, 248, 273 and 282 ( 12 ).…”

Molecular dynamics of dibenz[a,h]anthracene and its metabolite interacting with lung surfactant phospholipid bilayers

“…17,18 It is predicted that the potency of different diol epoxides is enhanced if they are in the ''bay'' region of the PAH molecules. 6,7 Therefore, it may be possible to generalize the fate of PAHs in the lung surfactant.…”

“…The surfactant forms a surface-active film composed of primarily phosphatidylcholine (PC) and phosphatidylglycerol (PG) that coat the air/water hypophase covering the alveolar tissue surface. 17,18 The metabolic activation of PAHs to carcinogens by cytochrome P450 has been investigated, showing that the epoxide, dihydrodiol, and diol epoxide structures are carcinogenic metabolites that attack DNA. By reducing the surface tension to low values during expiration, the surfactant stabilizes the lung at low volumes and limits the tendency to develop pulmonary edema.…”