Human DNA Polymerase ι Promotes Replication through a Ring-Closed Minor-Groove Adduct That Adopts a <i>syn</i> Conformation in DNA

Wolfle, William T.; Johnson, Robert E.; Minko, Irina G.; Lloyd, R. Stephen; Prakash, Satya; Prakash, Louise

doi:10.1128/mcb.25.19.8748-8754.2005

Cited by 42 publications

(68 citation statements)

References 29 publications

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“…It relies on Hoogsteen base pairing as opposed to typical WatsonCrick base pairing and thus operates with very low fidelity [107]. This mechanism may facilitate read-through of replication-blocking minor groove purine adducts [108]. In vivo, uracil derived from cytosine deamination may be the desired target of Polι as it inserts a G opposite a template U [109].…”

Section: Y Family Dna Polymerasesmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

185

187

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npg In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer. DNA damage toleranceIn the presence of spontaneous or carcinogen-induced DNA damage, living cells have to maintain and complete DNA synthesis or risk replication fork collapse. Since the process of DNA licensing is to ensure the genome is duplicated once and only once during each cell cycle, stalled or collapsed replication forks may not be able to restart, which often results in double-strand breaks (DSBs) and causes compromised genome integrity or cell death. In addition to highly conserved DNA repair pathways, all living organisms have evolved schemes to ensure continuation of DNA synthesis in the presence of damage. These schemes were originally termed DNA postreplication repair (PRR) due to observations of transient shortened nascent DNA structures following S phase in response to DNA damage. In bacteria and unicellular yeast, these shortened DNA segments can be measured by an alkaline sedimentation assay [1] or directly observed in electron micrographs [2]. In wild-type cells, these truncated DNA segments were restored to full length following a short recovery time. One typical experiment [1] involved the restoration of the nascent strand following UV exposure in nucleotide excision repair (NER)-deficient cells and was originally assumed to represent a mechanism of DNA repair. However, further investigation revealed that, although the nascent fragments were re-annealed, the original UV-induced pyrimidine dimers, which were responsible for the generation of single-strand gaps, often persisted in the genome [3,4]. It was argued that the replication-blocking lesion was not necessarily corrected, but rather transiently bypassed and carried over to the next generation. Perhaps it is more beneficial for the organi...

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Section: Y Family Dna Polymerasesmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

185

187

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“…In contrast to the inhibitory effects of the ring-closed analog of ␥-HOPdG on DNA synthesis by the various TLS Pols, the permanently ring-opened form of ␥-HOPdG does not present a significant block to synthesis by Pols , , or , as they can each carry out both nucleotide incorporation and the extension reactions opposite from it (33,54). Thus, we assume that an N 2 -dG minor-groove adduct, such as the ring-open form of ␥-HOPdG, can be accommodated in the active site of these Pols at both the nucleotide insertion and subsequent extension steps.…”

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confidence: 99%

“…Studies with the permanently ring-opened or ring-closed structural analogs of ␥-HOPdG have yielded useful information about the relative abilities of Pols , , and to replicate through such N 2 -dG adducts, and the combined results of these and other studies have indicated that these Pols vary in their response to different N 2 -dG adducts. For example, the ring-closed form of ␥-HOPdG is a strong block for nucleotide incorporation by Pols and , with only Pol being capable of inserting a C opposite from it (33,54). And, even though Pol can extend from a C opposite ␥-HOPdG, which can adopt both the ring-opened and ring-closed forms (51), it is unable to extend from the permanently ring-closed analog of ␥-HOPdG (54), suggesting that Pol can extend only if ␥-HOPdG is in the ring-opened conformation.…”

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confidence: 99%

A Role for Yeast and Human Translesion Synthesis DNA Polymerases in Promoting Replication through 3-Methyl Adenine

Johnson

Prakash

et al. 2007

Molecular and Cellular Biology

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3-Methyl adenine (3meA), a minor-groove DNA lesion, presents a strong block to synthesis by replicative DNA polymerases (Pols). To elucidate the means by which replication through this DNA lesion is mediated in eukaryotic cells, here we carry out genetic studies in the yeast Saccharomyces cerevisiae treated with the alkylating agent methyl methanesulfonate. From the studies presented here, we infer that replication through the 3meA lesion in yeast cells can be mediated by the action of three Rad6-Rad18-dependent pathways that include translesion synthesis (TLS) by Pol or -and an Mms2-Ubc13-Rad5-dependent pathway which presumably operates via template switching. We also express human Pols and in yeast cells and show that they too can mediate replication through the 3meA lesion in yeast cells, indicating a high degree of evolutionary conservation of the mechanisms that control TLS in yeast and human cells. We discuss these results in the context of previous observations that have been made for the roles of Pols , , and in promoting replication through the minor-groove N 2 -dG adducts.Replicative DNA polymerase (Pols) are highly sensitive to geometric distortions in DNA; consequently, they are inhibited by the presence of DNA lesions in the template strand. A number of Pols that promote replication through DNA lesions exist in eukaryotes, and they are highly specialized for the roles they play in translesion synthesis (TLS) (40). For example, both yeast and human Pols are highly adept at promoting error-free replication through UV-induced cyclobutane pyrimidine dimers (CPDs) (15,20,50,52), and inactivation of Pol in humans causes the cancer-prone syndrome of the variant form of xeroderma pigmentosum (14,30).Although proficient replication through a DNA lesion such as a CPD can be accomplished by Pol alone, replication through many of the different lesions present in DNA requires the sequential action of two Pols, in which one polymerase inserts the nucleotide opposite the DNA lesion and another polymerase performs the subsequent extension reaction (40,41). Yeast Pol, comprised of the Rev3 catalytic and Rev7 accessory subunits (39), is highly specialized for performing the extension step of TLS (8,19,21,35). Although humans also have the Rev3 and Rev7 proteins, there is no biochemical information available on the role of human Pol in TLS.In addition to Pol, humans have Pols and , which belong to the Y family of Pols (40). Pol differs strikingly from Pols and and almost all other Pols in that it incorporates nucleotides opposite template purines with much higher efficiency and fidelity than opposite template pyrimidines (6,19,44,49). Moreover, even opposite template purines, Pol exhibits higher catalytic efficiency and fidelity opposite template A than opposite template G. The ternary crystal structures of Pol bound to template A or G and the correct incoming deoxynucleoside triphosphate have shown that the purine template adopts a syn conformation in the Pol active site and forms a Hoogsteen base pair with the incom...

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“…1), have yielded the following observations and conclusions (28,30). (i) The ring-open form of ␥-HOPdG is not a block to synthesis by human Pol, Pol, or Pol at either the nucleotide incorporation step or the extension step.…”

mentioning

confidence: 99%

“…Since ␥-HOPdG can adopt a ring-closed cyclic form or a ring-open form in DNA, we also examined the ability of human Y family Pol (17) and Pol and Pol (30) to replicate through the structural analogs of ␥-HOPdG which permanently stay in the ring-closed or the ring-open form (Fig. 1).…”

mentioning

confidence: 99%

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

Wolfle

Johnson²,

Minko

et al. 2006

Molecular and Cellular Biology

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2minor-groove position of guanine. Previously, we have shown that proficient and error-free replication through the ␥-HOPdG (␥-hydroxy-1,N 2 -propano-2-deoxyguanosine) adduct, which is formed from the reaction of acrolein with the N 2 of guanine, is mediated by the sequential action of human Pol and Pol, in which Pol incorporates the nucleotide opposite the lesion site and Pol carries out the subsequent extension reaction. To test the general applicability of these observations to other adducts formed at the N 2 position of guanine, here we examine the proficiency of human Pol and Pol 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 ␥-HOPdG. We show here that the sequential action of Pol and Pol promotes efficient and error-free synthesis through the HNE-dG adducts, in which Pol incorporates the nucleotide opposite the lesion site and Pol performs the extension reaction.Lipid peroxidation is a chain reaction process that initiates from free radical attack on polyunsaturated fatty acids in membranes and results in the generation of a variety of highly reactive aldehydes: acrolein, crotonaldehyde, malonaldehyde, and trans-4-hydroxy-2-nonenal (HNE) (2,3,5,23). The N 2 group of guanine in DNA conjugates with these various aldehydes, resulting in adducts that are highly inhibitory to synthesis by replicative DNA polymerases (Pols) (12).The reaction of acrolein, an ␣,␤-unsaturated aldehyde, with the N 2 group of guanine in DNA followed by ring closure at N 1

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

Cited by 42 publications

References 29 publications

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

A Role for Yeast and Human Translesion Synthesis DNA Polymerases in Promoting Replication through 3-Methyl Adenine

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

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