Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma

Ströbel, Thomas; Madlener, Sibylle; Tuna, Serkan; Vose, Sarah; Lagerweij, Tonny; Würdinger, Thomas; Vierlinger, Klemens; Wöhrer, Adelheid; Price, Brendan D.; Demple, Bruce; Saydam, Okay; Saydam, Nurten

doi:10.1038/s41598-017-10013-w

Cited by 28 publications

(20 citation statements)

References 42 publications

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“…These data suggest that besides important roles in BER, AP nucleases also regulate HR in MM. These data are consistent with the observations in glioblastoma indicating the role of APEX1 in the regulation of HR 59 . However, our study further demonstrates that ability of both APEX1 and APEX2 to regulate HR can be partly attributed to their ability to regulate RAD51 expression in MM cells.…”

Section: Discussionsupporting

confidence: 93%

Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

Kumar

Talluri

Pal

et al. 2018

Blood Cancer Journal

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We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity. Regulation of HR by AP nucleases could be attributed, at least in part, to their ability to regulate recombinase (RAD51) expression. We also show that both nucleases interact with major HR regulators and that APEX1 is involved in P73-mediated regulation of RAD51 expression in MM cells. Consistent with the role in HR, we also show that AP-knockdown or treatment with inhibitor of AP nuclease activity increases sensitivity of MM cells to melphalan and PARP inhibitor. Importantly, although inhibition of AP nuclease activity increases cytotoxicity, it reduces genomic instability caused by melphalan. In summary, we show that APEX1 and APEX2, major BER proteins, also contribute to regulation of HR in MM. These data provide basis for potential use of AP nuclease inhibitors in combination with chemotherapeutics such as melphalan for synergistic cytotoxicity in MM.

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Section: Discussionsupporting

confidence: 93%

Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

Kumar

Talluri

Pal

et al. 2018

Blood Cancer Journal

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“…Oxidation of DNA repair proteins by RONS can act as a specific regulatory mechanism of protein structure and function (activation vs inhibition) [66,67]. Oxidative modification can also act to select a DNA repair pathway [5,68,69].…”

Section: Introductionmentioning

confidence: 99%

A new perspective on oxidation of DNA repair proteins and cancer

Alnajjar

Sweasy

2019

DNA Repair

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Reactive oxygen and nitrogen species (RONS) are formed as byproducts of many endogenous cellular processes, in response to infections, and upon exposure to various environmental factors. An increase in RONS can saturate the antioxidation system and leads to oxidative stress. Consequently, macromolecules are targeted for oxidative modifications, including DNA and protein. The oxidation of DNA, which leads to base modification and formation of abasic sites along with single and double strand breaks, has been extensively investigated. Protein oxidation is often neglected and is only recently being recognized as an important regulatory mechanism of various DNA repair proteins. This is a review of the current state of research on the regulation of DNA repair by protein oxidation with emphasis on the correlation between inflammation and cancer.

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“…DNA repair is associated with anticancer drug resistance, counteractant of radiotherapy, tumor aggressiveness, and poor prognosis, and inhibition of APE1 is thus a promising strategy for developing antitumor drugs [1][2][3] . Currently, several inhibitors that repress the nuclease activity of APE1 are under evaluation in different phases of clinical trials [1][2][3][4][5][6] . APE1 exerts its function in DNA repair through the nuclease domain which possesses both the endonuclease and the 3′-5′ exonuclease activity 7,8 .…”

mentioning

confidence: 99%

APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling

et al. 2021

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The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.

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Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma

Cited by 28 publications

References 42 publications

Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

A new perspective on oxidation of DNA repair proteins and cancer

APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling

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