Replicating Damaged DNA in Eukaryotes

Chatterjee, Nimrat; Siede, Wolfram

doi:10.1101/cshperspect.a019836

Cited by 13 publications

(11 citation statements)

References 167 publications

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“…Inhibition of Rad5 mediated lesion bypass activity by NSC109268 may also result in fork collapse leading to genetic instability – as shown here with reporter strain D7 – and finally cell death, thus mediating cellular sensitization to CP. It has been debated if the Rad5 mechanism is critical for S-phase progression in the presence of DNA damage, as suggested here, or acts predominantly in G2-phase to fill remaining single-stranded gaps [30,54-56]. The discrepancies in timing found in the literature may very well depend on level and kind of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…For the first time, this study shows an influence of phosphatases on the Rad5 tolerance pathway. Additionally, the notion of intertwined HR and TS pathways is supported [28,30,31]. Interestingly, the triple phosphatase mutant pph3Δptc2Δptc3Δ used by us was reported to be defective in early steps of HR [32] that may also be necessary for sister chromatid junction formation and processing within the Rad5 TS pathway [28,30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the notion of intertwined HR and TS pathways is supported [28,30,31]. Interestingly, the triple phosphatase mutant pph3Δptc2Δptc3Δ used by us was reported to be defective in early steps of HR [32] that may also be necessary for sister chromatid junction formation and processing within the Rad5 TS pathway [28,30,31]. Interestingly, Rpa2, a subunit of the single-strand DNA binding complex Replication Protein A, represents another target candidate since its phosphorylation status, which may be enhanced by NSC109268-mediated phosphatase inhibition, is inversely correlated with RAD51 foci formation [61].…”

Section: Discussionmentioning

confidence: 99%

“…Upon DNA damage, a lesion in the leading strand template can lead to uncoupling of leading and lagging strand synthesis and single-stranded DNA gaps can be found in both leading and lagging strands. Subsequently, strand invasion mediated by certain Homologous Recombination (HR) factors that include Rad51, Rad52, the complex of Rad55 - Rad57, promote the formation of TS intermediates that are dissolved by the action of the Sgs1-Top3 complex (Figure S1) [28,30,31]. …”

Section: Introductionmentioning

confidence: 99%

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Rad5 Template Switch Pathway of DNA Damage Tolerance Determines Synergism between Cisplatin and NSC109268 in Saccharomyces cerevisiae

Jain

Siede

2013

PLoS ONE

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The success of cisplatin (CP) based therapy is often hindered by acquisition of CP resistance. We isolated NSC109268 as a compound altering cellular sensitivity to DNA damaging agents. Previous investigation revealed an enhancement of CP sensitivity by NSC109268 in wild-type Saccharomyces cerevisiae and CP-sensitive and -resistant cancer cell lines that correlated with a slower S phase traversal. Here, we extended these studies to determine the target pathway(s) of NSC109268 in mediating CP sensitization, using yeast as a model. We reasoned that mutants defective in the relevant target of NSC109268 should be hypersensitive to CP and the sensitization effect by NSC109268 should be absent or strongly reduced. A survey of various yeast deletion mutants converged on the Rad5 pathway of DNA damage tolerance by template switching as the likely target pathway of NSC109268 in mediating cellular sensitization to CP. Additionally, cell cycle delays following CP treatment were not synergistically influenced by NSC109268 in the CP hypersensitive rad5Δ mutant. The involvement of the known inhibitory activities of NSC109268 on 20S proteasome and phosphatases 2Cα and 2A was tested. In the CP hypersensitive ptc2Δptc3Δpph3Δ yeast strain, deficient for 2C and 2A-type phosphatases, cellular sensitization to CP by NSC109268 was greatly reduced. It is therefore suggested that NSC109268 affects CP sensitivity by inhibiting the activity of unknown protein(s) whose dephosphorylation is required for the template switch pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rad5 Template Switch Pathway of DNA Damage Tolerance Determines Synergism between Cisplatin and NSC109268 in Saccharomyces cerevisiae

Jain

Siede

2013

PLoS ONE

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“…The insertion of the "incorrect" base is generally accomplished by substituting a "high fidelity" polymerase with a lower fidelity polymerase that also has lower processivity. The polymerase switch mechanism is accomplished by a series of ubiquitination reactions on PCNA, which is the processivity factor for DNA polymerase on the DNA template; for review, see [126,127]. The first ubiquitination reaction of PCNA is a monoubiquitination reaction catalyzed by Rad18/Rad6.…”

Section: Dna Damage Tolerance and Afb1-associated Dna Damagementioning

confidence: 99%

Cellular Responses to Aflatoxin-Associated DNA Adducts

Fasullo¹

2019

DNA Repair- An Update

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Aflatoxin B1 (AFB1) is the most potent known hepatocarcinogen. The signature p53 mutation (p53 249 ser) that is found in AFB1-associated liver cancer suggests that AFB1 is a potent genotoxin. AFB1 is not genotoxic per se but is metabolically activated by cytochrome P450 enzymes that convert the promutagen into a highly reactive epoxide, which primarily reacts with the N 7 group of guanine, forming 8,9-dihydro-8-(N 7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N 7-dG). While this primary adduct is unstable, the subsequent trans-8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy aflatoxin B1 (AFB1-Fapy)derived adducts are stable and are mutagenic. Studies have revealed that nucleotide excision repair (NER), base excision repair (BER), recombinational repair, and DNA replication bypass are all involved in conferring AFB1 resistance. To minimize the genotoxicity of AFB1, pathways function to detoxify the metabolically active intermediate, excise resulting DNA adducts, bypass unrepaired adducts, and repair secondary DNA breaks. How these repair pathways functionally cooperate to minimize AFB1-associated genetic instability phenotypes is not well understood. Insights can be gained from epidemiological research and model organisms. Gene profiling and next-generation sequencing are facilitating how pathways and tissuespecific differences are induced. This review will encompass studies concerning human genetic susceptibility to AFB1 and pathways that repair and tolerate AFB1associated DNA damage.

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DNA Interstrand Crosslink Repair

Siede¹

2020

Encyclopedia of Life Sciences

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Crosslinking agents such as psoralens, nitrogen mustards or cisplatin are bifunctionally acting chemicals that generate some adducts as covalent linkages between complementary deoxyribonucleic acid strands. Since many agents are of importance in genetic toxicology and cancer therapy, repair of interstrand crosslinks has been studied extensively in bacteria and in lower and higher eukaryotes. The main repair pathway in Escherichia coli involves the sequential action of nucleotide excision repair and recombinational repair. In eukaryotes, nucleotide excision repair, translesion synthesis and homologous recombination all play important roles in crosslink repair. Instances where crosslink unhooking is performed by a glycosylase have also been observed. The relative pathway contribution depends on cell cycle position and agent used. Analysis of mammalian crosslink response proteins that are also involved in the hereditary syndrome Fanconi anaemia resulted in a model of crosslink repair within the context of converging replicons arrested by an interstrand crosslink. Key Concepts Certain chemicals with two or more correctly spaced reactive groups can covalently link opposing DNA strands. Several repair or tolerance pathways such as nucleotide excision repair, homologous recombination, translesion synthesis and even DNA glycosylases can work together to overcome such complex damage. Cell cycle stage may determine the choice of repair pathway or pathway combinations. A heritable human cancer‐prone syndrome with diverse phenotypes (Fanconi anaemia) has been linked to defects in crosslink repair. By integrating in vitro studies and the analysis of Fanconi proteins, a model for mammalian cells places replication‐coupled crosslink repair at the convergence point of stalled replication forks. This model includes a sequence of unhooking of the interstrand crosslink by structure‐specific endonucleases, filling of the created single‐stranded gap by translesion synthesis and repair of the double‐strand break in the sister chromatid by one of several pathways, including homologous recombination.

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Replicating Damaged DNA in Eukaryotes

Cited by 13 publications

References 167 publications

Rad5 Template Switch Pathway of DNA Damage Tolerance Determines Synergism between Cisplatin and NSC109268 in Saccharomyces cerevisiae

Rad5 Template Switch Pathway of DNA Damage Tolerance Determines Synergism between Cisplatin and NSC109268 in Saccharomyces cerevisiae

Cellular Responses to Aflatoxin-Associated DNA Adducts

DNA Interstrand Crosslink Repair

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