Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links

Minko, Irina G.; Harbut, Michael B.; Kozekov, Ivan D.; Kozekova, Albena; Jakobs, Petra M.; Olson, Susan B.; Moses, Robb E.; Harris, Thomas M.; Rizzo, Carmelo J.; Lloyd, R. Stephen

doi:10.1074/jbc.m801238200

Cited by 121 publications

(197 citation statements)

References 48 publications

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“…Pol k was shown to catalyze accurate bypass of N 2 -N 2 -guanine ICL in vitro, and Pol k-depleted cells show chromosome instability and decreased survival following MMC exposure (Minko et al 2008). The A family Pol u (POLQ) can extend DNA from mismatched bases in vitro (Seki and Wood 2008).…”

Section: Tls Polymerases In Icl Repairmentioning

confidence: 99%

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Kim¹,

D’Andrea²

2012

Genes Dev.

443

499

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The maintenance of genome stability is critical for survival, and its failure is often associated with tumorigenesis. The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links (ICLs), and a germline defect in the pathway results in FA, a cancer predisposition syndrome driven by genome instability. Central to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities required for the resolution of ICLs. Recent studies have demonstrated how the FA pathway coordinates three critical DNA repair processes, including nucleolytic incision, translesion DNA synthesis (TLS), and homologous recombination (HR). Here, we review recent advances in our understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation.

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Section: Tls Polymerases In Icl Repairmentioning

confidence: 99%

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Kim¹,

D’Andrea²

2012

Genes Dev.

443

499

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“…1A) containing various model acrolein-mediated N 2 -N 2 -guanine cross-links (see Fig. 1B) were synthesized and purified as previously described (6) Proteins-E. coli pol II and pol IV were purified as described previously (9,10).…”

Section: Generation Of Oligodeoxynucleotides Containing Site-specificmentioning

confidence: 99%

“…These investigations revealed that pol was able to catalyze bypass of ICL lesions in which the nucleotides 3Ј to the lesion had been removed (6).…”

mentioning

confidence: 99%

Replication Bypass of Interstrand Cross-link Intermediates by Escherichia coli DNA Polymerase IV

Kumari

Minko

Harbut

et al. 2008

Journal of Biological Chemistry

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Repair of interstrand DNA cross-links (ICLs) in Escherichia coli can occur through a combination of nucleotide excision repair (NER) and homologous recombination. However, an alternative mechanism has been proposed in which repair is initiated by NER followed by translesion DNA synthesis (TLS) and completed through another round of NER. Using site-specifically modified oligodeoxynucleotides that serve as a model for potential repair intermediates following incision by E. coli NER proteins, the ability of E. coli DNA polymerases (pol) II and IV to catalyze TLS past N 2 -N 2 -guanine ICLs was determined. No biochemical evidence was found suggesting that pol II could bypass these lesions. In contrast, pol IV could catalyze TLS when the nucleotides that are 5 to the cross-link were removed. The efficiency of TLS was further increased when the nucleotides 3 to the cross-linked site were also removed. The correct nucleotide, C, was preferentially incorporated opposite the lesion. When E. coli cells were transformed with a vector carrying a site-specific N 2 -N 2 -guanine ICL, the transformation efficiency of a pol II-deficient strain was indistinguishable from that of the wild type. However, the ability to replicate the modified vector DNA was nearly abolished in a pol IV-deficient strain. These data strongly suggest that pol IV is responsible for TLS past N 2 -N 2 -guanine ICLs.Interstrand DNA cross-links (ICLs) 2 represent a major challenge to cellular survival by virtue of their ability to block progression of DNA replication and transcription. In Escherichia coli, biochemical and genetic data support a mechanism by which ICLs can be repaired through the combined activities associated with the nucleotide excision repair (NER) pathway and the homologous recombination (HR) damage avoidance pathway (1). The overall pathway requires recognition and initiation of ICL repair by the action of UvrABC, creating dual incisions by hydrolyzing the ninth phosphodiester bond 5Ј and the third phosphodiester bond 3Ј to the cross-link (2, 3). It has been proposed that this "unhooked" DNA can be structurally manipulated such that HR-driven strand invasion occurs via pairing with the intact strand that is still physically linked to the incised strand. Subsequent to recombination, in which a nondamaged homologous strand is positioned opposite the crosslinked strand, a second round of NER can excise the remaining damage, followed by gap synthesis and ligation.Although the above mechanism has the capacity to fully repair ICL-containing DNA, an alternative pathway not requiring HR has been proposed (4, 5). This pathway utilizes the activity of the polB gene product, DNA polymerase (pol) II. The data demonstrated that pol II, but not pol IV or V, was functioning in this HR-independent ICL repair pathway. It was hypothesized that pol II could catalyze replication bypass of the incised but still covalently linked DNA (4, 5). However, no biochemical data supporting such an activity of pol II have subsequently appeared.Using a series of synth...

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“…Interstrand cross-links create complete obstructions of these fundamental DNA metabolic processes, leading to potent genotoxicity. Importantly, ICLs can arise from exogenous agents such as the anticancer drugs cisplatin and mitomycin C (MMC) and endogenous sources in the form of by-products of metabolic processes (4). In general, these agents also form intrastrand cross-links (5).…”

mentioning

confidence: 99%

Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability

Sparks

Kumar

Singh

et al. 2012

Journal of Biological Chemistry

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Background: Deoxyribonucleases are key DNA metabolic enzymes, but their functions remain ill defined. Results: Human EXO5 is a novel bidirectional single strand-specific sliding exonuclease; however, RPA enforces a 5Ј-directionality of nuclease activity. Conclusion: hEXO5 functions in nuclear genome maintenance and interstrand cross-link repair. Significance: Nucleases are important in directing pathway choices at DNA damage and replication blocks.

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Role for DNA Polymerase κ in the Processing of N2-N2-Guanine Interstrand Cross-links

Cited by 121 publications

References 48 publications

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Replication Bypass of Interstrand Cross-link Intermediates by Escherichia coli DNA Polymerase IV

Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability

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