Replication by human DNA polymerase-ι occurs by Hoogsteen base-pairing

Nature ◽  
2004 ◽  
Vol 430 (6997) ◽  
pp. 377-380 ◽  
Author(s):  
Deepak T. Nair ◽  
Robert E. Johnson ◽  
Satya Prakash ◽  
Louise Prakash ◽  
Aneel K. Aggarwal
Keyword(s):  
Dna Polymerase ◽  
Base Pairing ◽  
Human Dna ◽  
Hoogsteen Base Pairing ◽  
Dna Polymerase Ι

scholarly journals Mutagenesis mechanism of the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine

2020 ◽  
Vol 48 (9) ◽  
pp. 5119-5134 ◽  
Author(s):  
Myong-Chul Koag ◽  
Hunmin Jung ◽  
Seongmin Lee
Keyword(s):  
Reactive Oxygen Species ◽  
Crystal Structures ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Reactive Oxygen ◽  
Minor Groove ◽  
Oxygen Species ◽  
Base Pairing ◽  
Human Dna ◽  
Hoogsteen Base Pairing

Abstract Reactive oxygen species generate the genotoxic 8-oxoguanine (oxoG) and 8-oxoadenine (oxoA) as major oxidative lesions. The mutagenicity of oxoG is attributed to the lesion's ability to evade the geometric discrimination of DNA polymerases by adopting Hoogsteen base pairing with adenine in a Watson–Crick-like geometry. Compared with oxoG, the mutagenesis mechanism of oxoA, which preferentially induces A-to-C mutations, is poorly understood. In the absence of protein contacts, oxoA:G forms a wobble conformation, the formation of which is suppressed in the catalytic site of most DNA polymerases. Interestingly, human DNA polymerase η (polη) proficiently incorporates dGTP opposite oxoA, suggesting the nascent oxoA:dGTP overcomes the geometric discrimination of polη. To gain insights into oxoA-mediated mutagenesis, we determined crystal structures of polη bypassing oxoA. When paired with dGTP, oxoA adopted a syn-conformation and formed Hoogsteen pairing while in a wobble geometry, which was stabilized by Gln38-mediated minor groove contacts to oxoA:dGTP. Gln38Ala mutation reduced misinsertion efficiency ∼55-fold, indicating oxoA:dGTP misincorporation was promoted by minor groove interactions. Also, the efficiency of oxoA:dGTP insertion by the X-family polβ decreased ∼380-fold when Asn279-mediated minor groove contact to dGTP was abolished. Overall, these results suggest that, unlike oxoG, oxoA-mediated mutagenesis is greatly induced by minor groove interactions.

scholarly journals Replication past a trans-4-Hydroxynonenal Minor-Groove Adduct by the Sequential Action of Human DNA Polymerases ι and κ

2006 ◽  
Vol 26 (1) ◽  
pp. 381-386 ◽  
Author(s):  
William T. Wolfle ◽  
Robert E. Johnson ◽  
Irina G. Minko ◽  
R. Stephen Lloyd ◽  
Satya Prakash ◽  
...  
Keyword(s):  
Dna Polymerases ◽  
Minor Groove ◽  
Structural Features ◽  
Lesion Site ◽  
Base Pairing ◽  
General Applicability ◽  
Sequential Action ◽  
Human Dna ◽  
Hoogsteen Base Pairing ◽  
Dna Polymerase Ι

ABSTRACT The X-ray crystal structure of human DNA polymerase ι (Polι) has shown that it differs from all known Pols in its dependence upon Hoogsteen base pairing for synthesizing DNA. Hoogsteen base pairing provides an elegant mechanism for synthesizing DNA opposite minor-groove adducts that present a severe block to synthesis by replicative DNA polymerases. Germane to this problem, a variety of DNA adducts form at the N2 minor-groove position of guanine. Previously, we have shown that proficient and error-free replication through the γ-HOPdG (γ-hydroxy-1,N 2-propano-2′-deoxyguanosine) adduct, which is formed from the reaction of acrolein with the N2 of guanine, is mediated by the sequential action of human Polι and Polκ, in which Polι incorporates the nucleotide opposite the lesion site and Polκ carries out the subsequent extension reaction. To test the general applicability of these observations to other adducts formed at the N2 position of guanine, here we examine the proficiency of human Polι and Polκ to synthesize past stereoisomers of trans-4-hydroxy-2-nonenal-deoxyguanosine (HNE-dG). Even though HNE- and acrolein-modified dGs share common structural features, due to their increased size and other structural differences, HNE adducts are potentially more blocking for replication than γ-HOPdG. We show here that the sequential action of Polι and Polκ promotes efficient and error-free synthesis through the HNE-dG adducts, in which Polι incorporates the nucleotide opposite the lesion site and Polκ performs the extension reaction.

scholarly journals Human DNA Polymerase ι Incorporates dCTP Opposite Template G via a G.C+ Hoogsteen Base Pair

Structure ◽  
2005 ◽  
Vol 13 (10) ◽  
pp. 1569-1577 ◽  
Author(s):  
Deepak T. Nair ◽  
Robert E. Johnson ◽  
Louise Prakash ◽  
Satya Prakash ◽  
Aneel K. Aggarwal
Keyword(s):  
Dna Polymerase ◽  
Base Pair ◽  
Human Dna ◽  
Dna Polymerase Ι

Response of human DNA polymerase ι promoter to N-methyl-N′-nitro-N-nitrosoguanidine

2010 ◽  
Vol 29 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Huifang Zhu ◽  
Yanfeng Fan ◽  
Hongjuan Jiang ◽  
Jing Shen ◽  
Hongyan Qi ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Human Dna ◽  
Dna Polymerase Ι

scholarly journals Human DNA Polymerase ι Promotes Replication through a Ring-Closed Minor-Groove Adduct That Adopts a syn Conformation in DNA

2005 ◽  
Vol 25 (19) ◽  
pp. 8748-8754 ◽  
Author(s):  
William T. Wolfle ◽  
Robert E. Johnson ◽  
Irina G. Minko ◽  
R. Stephen Lloyd ◽  
Satya Prakash ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Polymerases ◽  
Minor Groove ◽  
Dna Lesions ◽  
Unsaturated Aldehyde ◽  
Cyclic Form ◽  
Human Dna ◽  
A Minor ◽  
Dna Polymerase Ι

ABSTRACT Acrolein, an α,β-unsaturated aldehyde, is generated in vivo as the end product of lipid peroxidation and from oxidation of polyamines. The reaction of acrolein with the N 2 group of guanine in DNA leads to the formation of a cyclic adduct, γ-hydroxy-1,N 2-propano-2′-deoxyguanosine (γ-HOPdG). Previously, we have shown that proficient replication through the γ-HOPdG adduct can be mediated by the sequential action of human DNA polymerases (Pols) ι and κ, in which Polι incorporates either pyrimidine opposite γ-HOPdG, but Polκ extends only from the cytosine. Since γ-HOPdG can adopt either a ring-closed cyclic form or a ring-opened form in DNA, to better understand the mechanisms that Pols ι and κ employ to promote replication through this lesion, we have examined the ability of these polymerases to replicate through the structural analogs of γ-HOPdG that are permanently either ring closed or ring opened. Our studies with these model adducts show that whereas the ring-opened form of γ-HOPdG is not inhibitory to synthesis by human Pols η, ι, or κ, only Polι is able to incorporate nucleotides opposite the ring-closed form, which is known to adopt a syn conformation in DNA. From these studies, we infer that (i) Pols η, ι, and κ have the ability to proficiently replicate through minor-groove DNA lesions that do not perturb the Watson-Crick hydrogen bonding of the template base with the incoming nucleotide, and (ii) Polι can accommodate a minor-groove-adducted template purine which adopts a syn conformation in DNA and forms a Hoogsteen base pair with the incoming nucleotide.

Roles of the active site residues and metal cofactors in noncanonical base-pairing during catalysis by human DNA polymerase iota

DNA Repair ◽  
2014 ◽  
Vol 22 ◽  
pp. 67-76 ◽  
Author(s):  
Alena V. Makarova ◽  
Artem Ignatov ◽  
Nataliya Miropolskaya ◽  
Andrey Kulbachinskiy
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Active Site Residues ◽  
Base Pairing ◽  
Dna Polymerase Iota ◽  
Human Dna ◽  
Metal Cofactors
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