POLI incorporates dNMP opposite to damaged DNA base

Stable Identifier
R-HSA-5656148
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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DNA polymerase iota (POLI) has an active site that favours Hoogsteen base pairing instead of Watson-Crick base pairing. POLI has the highest efficiency and fidelity in incorporating dTTP opposite to a template adenine (A). The active site of POLI causes the template A to rotate about its glycosidic bond and acquire a syn conformation. The hydrogen bonds are then established between the Hoogsteen edge of the template A in syn conformation (N7 and N6) and the Watson-Crick edge of dTMP (N3 and O4), which remains in anti conformation. POLI shows lower efficiency in incorporating dCTP opposite the template guanine (G) (Nair et al. 2004).


Hoogsteen base pairing and rotation of template purines from anti to syn conformation serves as a mechanism to displace adducts on template G or template A that interfere with DNA replication, as is the case with gamma-hydroxy-1,N2-propano-2'deoxyguanosine (gamma-HOPdG), or to allow base pairing of damaged purines with a disrupted Watson-Crick edge but an intact Hoogsteen edge, as is the case with 1,N6-ethenodeoxyadenosine (EtAD) (Nair et al. 2006).


Gamma-HOPdG is formed when acrolein, an alpha,beta-unsaturated aldehyde generated as an end product of lipid peroxidation or oxidation of polyamines, reacts with the N2 of guanine, leading to formation of a cyclic adduct. POLI incorporates dCMP opposite gamma-HOPdG as efficiently as opposite an undamaged G (Washington et al. 2004). EtAD is generated when DNA is exposed to chemical carcinogens, such as vinyl chloride, or epoxyaldehydes that are produced by lipid peroxidation. POLI shows preferential dTMP incorporation opposite to a template EtAD, but can also erroneously incorporate dCMP although with four times lower efficiency (Nair et al. 2006).

Literature References
PubMed ID Title Journal Year
16819516 Hoogsteen base pair formation promotes synthesis opposite the 1,N6-ethenodeoxyadenosine lesion by human DNA polymerase iota

Nair, DT, Johnson, RE, Prakash, L, Prakash, S, Aggarwal, AK

Nat. Struct. Mol. Biol. 2006
15254543 Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing

Nair, DT, Johnson, RE, Prakash, S, Prakash, L, Aggarwal, AK

Nature 2004
15199127 Efficient and error-free replication past a minor-groove DNA adduct by the sequential action of human DNA polymerases iota and kappa

Washington, MT, Minko, IG, Johnson, RE, Wolfle, WT, Harris, TM, Lloyd, RS, Prakash, S, Prakash, L

Mol. Cell. Biol. 2004
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Catalyst Activity
Title
DNA-directed DNA polymerase activity of POLI:REV1:POLZ:MonoUb:K164-PCNA:RPA:RFC:EtAD-DNA Template,Gamma-HOPdG-DNA Template [nucleoplasm]
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Activity
Orthologous Events
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