Review
Biochemistry & Molecular Biology
David J. Lopez, Jose A. Rodriguez, Sonia Banuelos
Summary: APE1, a crucial enzyme in DNA repair pathways, has additional functions beyond its endonuclease activity, including redox regulation of transcription factors and involvement in RNA metabolism. The N-terminal region of APE1 plays a significant role in regulating its function, particularly through interactions with nucleophosmin.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Nicole M. Hoitsma, Timothy H. Click, Pratul K. Agarwal, Bret D. Freudenthal
Summary: The study provides insights into the processing of abasic ribonucleotides (rAPs) by APE1, revealing a decrease in activity compared to canonical deoxy-AP substrates. Novel contacts between rAP and the APE1 active site were identified using X-ray crystallography, showing accommodation of the rAP sugar pucker in a C3'-endo conformation. This work advances the understanding of ribonucleotide processing within genomic DNA.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Anastasiia T. Davletgildeeva, Alexandra A. Kuznetsova, Darya S. Novopashina, Alexander A. Ishchenko, Murat Saparbaev, Olga S. Fedorova, Nikita A. Kuznetsov
Summary: AP-endonucleases are multifunctional enzymes that are required for cell viability. In this study, the effect of metal ions on the exo- and endonuclease activities of four homologous APE1-like endonucleases was analyzed. It was found that these enzymes showed similar dependence patterns on metal ions' concentrations in terms of AP-endonuclease activity. The efficiency of the 3'-5' exonuclease activity was highest in hAPE1, while the endoribonuclease activity varied among the enzymes. These findings indicate that substrate specificity and cleavage efficiency are controlled by factors external to the catalytic site.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Anastasiia T. Davletgildeeva, Alexander A. Ishchenko, Murat Saparbaev, Olga S. Fedorova, Nikita A. Kuznetsov
Summary: The study compared conformational changes of three homologous APE1-like endonucleases during their interaction with different damaged DNA substrates, outlining a model of substrate recognition by this class of enzymes. Differences in rates of DNA substrate binding did not significantly affect cleavage efficiency, indicating that enzyme-substrate complex formation is not the limiting factor for enzyme turnover; mechanisms of damage recognition and cleavage efficacy are related to fine conformational tuning inside the active site.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Tyler M. Weaver, Nicole M. Hoitsma, Jonah J. Spencer, Lokesh Gakhar, Nicholas J. Schnicker, Bret D. Freudenthal
Summary: This study reveals the mechanism by which base excision repair proteins recognize and repair DNA damage in the nucleosome. Exposed DNA damage sites in the nucleosome are cleaved more efficiently by repair enzymes compared to occluded sites. Contacts between nucleosomal DNA and histones hinder the efficient processing of DNA damage sites by repair enzymes.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Nina Komaniecka, Marta Porras, Louis Cairn, Jon Ander Santas, Nerea Ferreiro, Juan Carlos Penedo, Sonia Banuelos
Summary: APE1 is a key enzyme in the BER pathway, involved in repairing oxidative DNA damage. Its structure includes a catalytic domain and a flexible N-terminal extension. Conformational rearrangements occur internally and between molecules when APE1 binds DNA and interacts with NPM1. These findings suggest that the N-terminal region approaches the DNA near the abasic site, and its spatial configuration is sensitive to NPM1, potentially impacting APE1's regulation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Alexandra A. Kuznetsova, Svetlana Senchurova, Alexander A. Ishchenko, Murat Saparbaev, Olga S. Fedorova, Nikita A. Kuznetsov
Summary: The study revealed that structurally different AP endonucleases Nfo and APE1 utilize a common strategy of damage recognition controlled by enzyme conformational transitions after initial DNA binding. Local stability of the DNA duplex near the lesion affects catalytic-complex formation and DNA cleavage efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Arianna Barchiesi, Veronica Bazzani, Agata Jabczynska, Lukasz S. Borowski, Silke Oeljeklaus, Bettina Warscheid, Agnieszka Chacinska, Roman J. Szczesny, Carlo Vascotto
Summary: APE1 is a versatile protein involved in DNA repair, gene expression regulation, and RNA metabolism in mitochondria. Loss of APE1 leads to accumulation of damaged mitochondrial mRNA, impairing protein translation and mitochondrial respiration efficiency. The data demonstrate that APE1 plays a crucial role in maintaining mitochondrial well-being.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Jonathan Dorival, Brandt F. Eichman
Summary: This study reveals the nuclease activities of human TatD paralogs TATDN1 and TATDN3, which include both 3'-5' exonuclease activity and AP endonuclease activity. The two nuclease activities are exhibited in different types of DNA and are regulated by divalent metal cofactors. The study also shows that the three E. coli TatD paralogs also possess AP endonuclease activity.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Medicinal
Yi Yuan, Dingqiang Fu, Yan Xu, Xuyang Wang, Xiongfei Deng, Shan Zhou, Feng Du, Xin Cui, Yun Deng, Zhuo Tang
Summary: This study describes a novel Pt(IV) prodrug, AP1, that targets the BER protein APE1 and induces DNA damage response and apoptosis in cancer cells. AP1 shows strong inhibitory effects on malignant cells, including cisplatin-resistant cells, with minimal toxicity to normal cells. It can also directly inhibit the activity of APE1 and interrupt miRNA processing, leading to the upregulation of the tumor suppressor PTEN.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Aneta Kohutova, Dita Münzova, Martin Pesl, Vladimir Rotrekl
Summary: Methoxamine hydrochloride is a known inhibitor of base excision repair (BER) that acts by inhibiting APE1, an endonuclease enzyme. This study demonstrates the weaker but still significant effect of Methoxamine compared to the known BER inhibitor methoxyamine. The relative IC50 of Methoxamine was determined to be 19 mmol L-1, indicating its clinically relevant impact on APE1 activity.
ACTA PHARMACEUTICA
(2023)
Article
Biochemistry & Molecular Biology
Amy M. Whitaker, Wesley J. Stark, Bret D. Freudenthal
Summary: Reactive oxygen species can cause DNA damage, leading to changes in its base-pairing properties and genetic mutations that contribute to cancer and other diseases. Base excision repair (BER) is a key pathway for repairing DNA base damage, with the enzyme APE1 playing a crucial role in DNA cleavage. This study used X-ray crystallography to investigate the exonuclease (exo) activity of APE1 on 3'-8-oxoG substrates, revealing a different mechanism from its AP-endonuclease activity. By combining structural data with enzyme kinetics and binding studies, unique protein:DNA interactions involved in the removal of 8-oxoG by APE1 were identified and characterized.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Giovanna Mangiapane, Isabella Parolini, Kristel Conte, Matilde Clarissa Malfatti, Jessica Corsi, Massimo Sanchez, Agostina Pietrantoni, Vito G. D'Agostino, Gianluca Tell
Summary: The study elucidated the mechanisms by which APE1 is secreted through exosomes and revealed its delivery in response to genotoxic stresses, shedding new light on its noncanonical biological functions in cancer biology.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Anatoly A. Bulygin, Olga S. Fedorova, Nikita A. Kuznetsov
Summary: AP endonucleases are crucial DNA repair enzymes that exhibit broad substrate specificity for repairing AP sites and various damaged bases. A computational study on several homologous APE1-like endonucleases revealed that amino acid residues in the active site and the damage recognition loop significantly affect catalytic complex formation and the efficiency of cleaving different damaged nucleotides.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Kaili Long, Lili Gu, Lulu Li, Ziyu Zhang, Enjie Li, Yilan Zhang, Lingfeng He, Feiyan Pan, Zhigang Guo, Zhigang Hu
Summary: APE1 plays a critical role in NSCLC and its inhibitor NO.0449-0145 induces DNA damage and cell death, overcoming resistance to traditional chemotherapy in NSCLC cells. These findings highlight the therapeutic potential of targeting APE1 in NSCLC and developing small-molecule drugs for the treatment of other cancers.
CELL DEATH & DISEASE
(2021)