The DNA damage-sensing NER repair factor XPC-RAD23B does not recognize bulky DNA lesions with a missing nucleotide opposite the lesion

Feher, Katie M.; Kolbanovskiy, Alexander; Durandin, Alexander; Shim, Yoonjung; Min, Jo Young; Lee, Yuan Cho; Shafirovich, Vladimir; Mu, Hong; Broyde, Suse; Geacintov, Nicholas E.

doi:10.1016/j.dnarep.2020.102985

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…There were several reasons to choose the E. coli system to demonstrate the clear picture of the dG-AF adduct’s biological properties in cell; first, a single-stranded DNA vector was chosen to avoid repair of the bulky dG-AF adduct that would be recognized by NER proteins such as XPC in specific secondary structures, namely the single strand–double strand DNA junction ( 49–51 ). Thus, the cellular data reflected the biological properties of dG-AF adduct without complications from NER repair.…”

Section: Resultsmentioning

confidence: 99%

Conformation-dependent lesion bypass of bulky arylamine-dG adducts generated from 2-nitrofluorene in epigenetic sequence contexts

Crisalli,

Chen,

Cai

et al. 2023

Nucleic Acids Research

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Sequence context influences structural characteristics and repair of DNA adducts, but there is limited information on how epigenetic modulation affects conformational heterogeneity and bypass of DNA lesions. Lesions derived from the environmental pollutant 2-nitrofluorene have been extensively studied as chemical carcinogenesis models; they adopt a sequence-dependent mix of two significant conformers: major groove binding (B) and base-displaced stacked (S). We report a conformation-dependent bypass of the N-(2′-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene (dG-FAF) lesion in epigenetic sequence contexts (d[5′-CTTCTC#G*NCCTCATTC-3′], where C# is C or 5-methylcytosine (5mC), G* is G or G-FAF, and N is A, T, C or G). FAF-modified sequences with a 3′ flanking pyrimidine were better bypassed when the 5′ base was 5mC, whereas sequences with a 3′ purine exhibited the opposite effect. The conformational basis behind these variations differed; for -CG*C- and -CG*T-, bypass appeared to be inversely correlated with population of the duplex-destabilizing S conformer. On the other hand, the connection between conformation and a decrease in bypass for flanking purines in the 5mC sequences relative to C was more complex. It could be related to the emergence of a disruptive non-S/B conformation. The present work provides novel conformational insight into how 5mC influences the bypass efficiency of bulky DNA damage.

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Section: Resultsmentioning

confidence: 99%

Conformation-dependent lesion bypass of bulky arylamine-dG adducts generated from 2-nitrofluorene in epigenetic sequence contexts

Crisalli,

Chen,

Cai

et al. 2023

Nucleic Acids Research

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“…The protein XPA plays a structural role in the assembly of this multi-protein-DNA complex [ 33 ] that, in turn, recruits the endonucleases XPF and XPG that catalyze the dual incisions of these oligonucleotide sequences that is followed by the excision of oligonucleotides ~24–32 nucleotides in length. We employed standard Western Blot methods for comparing the expressions of three of the critically important TFIIH proteins XPA, XPB and XPD in BRBE-treated and untreated HeLa cells; XPC-Rad23B was omitted because the binding affinity of XPC-Rad23B to structurally distorted DNA sequences is not proportional to the overall observed NER dual incision efficiencies [ 34 ], and because of its affinity for binding to unmodified DNA and to structural DNA distortions even in the absence of DNA lesions or adducts [ 34 , 35 , 36 ].…”

Section: Resultsmentioning

confidence: 99%

“…We reasoned that Gh would be interesting to study because the BER and NER mechanisms appear to compete for excising the same lesion [ 24 , 34 ]. In our experiments, the BER activity of Gh in our DNA repair pathways are robust ( Figure 3 A) and overshadows the NER activity.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Human HeLa Cells with Black Raspberry Extracts Enhances the Removal of DNA Lesions by the Nucleotide Excision Repair Mechanism

et al. 2022

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As demonstrated by us earlier and by other researchers, a diet containing freeze-dried black raspberries (BRB) inhibits DNA damage and carcinogenesis in animal models. We tested the hypothesis that the inhibition of DNA damage by BRB is due, in part, to the enhancement of DNA repair capacity evaluated in the human HeLa cell extract system, an established in vitro system for the assessment of cellular DNA repair activity. The pre-treatment of intact HeLa cells with BRB extracts (BRBE) enhances the nucleotide excision repair (NER) of a bulky deoxyguanosine adduct derived from the polycyclic aromatic carcinogen benzo[a]pyrene (BP-dG) by ~24%. The NER activity of an oxidatively-derived non-bulky DNA lesion, guanidinohydantoin (Gh), is also enhanced by ~24%, while its base excision repair activity is enhanced by only ~6%. Western Blot experiments indicate that the expression of selected, NER factors is also increased by BRBE treatment by ~73% (XPA), ~55% (XPB), while its effects on XPD was modest (<14%). These results demonstrate that BRBE significantly enhances the NER yields of a bulky and a non-bulky DNA lesion, and that this effect is correlated with an enhancement of expression of the critically important NER factor XPA and the helicase XPB, but not the helicase XPD.

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“…Like other repair systems, there are two steps involved: recognition of the damage and the reparation step. Bulky adducts cause DNA distortions recognized by XPC-RAD23B, but only if the nucleotide opposing the lesion is not missing [ 15 ]. Once XPC-RAD23B recognizes the bulky adduct, a small bubble is formed, and TFIIH, a complex of 10 proteins, is recruited [ 16 ].…”

Section: The Dna Damage Responsementioning

confidence: 99%

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

Jurkovičová

Neophytou²,

Gašparović³

et al. 2022

IJMS

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Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients’ prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.

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The DNA damage-sensing NER repair factor XPC-RAD23B does not recognize bulky DNA lesions with a missing nucleotide opposite the lesion

Cited by 5 publications

References 47 publications

Conformation-dependent lesion bypass of bulky arylamine-dG adducts generated from 2-nitrofluorene in epigenetic sequence contexts

Conformation-dependent lesion bypass of bulky arylamine-dG adducts generated from 2-nitrofluorene in epigenetic sequence contexts

Treatment of Human HeLa Cells with Black Raspberry Extracts Enhances the Removal of DNA Lesions by the Nucleotide Excision Repair Mechanism

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

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