Apurinic/Apyrimidinic Endonuclease 2 (APE2): An ancillary enzyme for contextual base excision repair mechanisms to preserve genome stability

Chaudhari, Sima; Ware, Akshay P.; Jayaram, Pradyumna; Gorthi, Sankar Prasad; El‐Khamisy, Sherif F.; Satyamoorthy, Kapaettu

doi:10.1016/j.biochi.2021.07.006

Cited by 8 publications

(8 citation statements)

References 158 publications

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“…APE2 deficiency causes severe defects in lymphopoiesis, and prevents B cell progenitors from proliferating in the bone marrow, indicating that APE2 also plays a role in adaptive immunity. APE2 expression is also increased in GC B cells, and protects proliferating B cells from oxidative damage (111,(122)(123)(124)(125)(126)(127). Guikema et al demonstrated that APE1 and APE2 are essential for CSR, as a decrease in this process was observed in splenic B cells of ape1 +/− , ape2 Y/− , and doubledeficient mice compared to wild type mice (122).…”

Section: Ape1 In Adaptive Immunitymentioning

confidence: 99%

APE1/Ref-1 Role in Inflammation and Immune Response

et al. 2022

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Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme that is essential for maintaining cellular homeostasis. APE1 is the major apurinic/apyrimidinic endonuclease in the base excision repair pathway and acts as a redox-dependent regulator of several transcription factors, including NF-κB, AP-1, HIF-1α, and STAT3. These functions render APE1 vital to regulating cell signaling, senescence, and inflammatory pathways. In addition to regulating cytokine and chemokine expression through activation of redox sensitive transcription factors, APE1 participates in other critical processes in the immune response, including production of reactive oxygen species and class switch recombination. Furthermore, through participation in active chromatin demethylation, the repair function of APE1 also regulates transcription of some genes, including cytokines such as TNFα. The multiple functions of APE1 make it an essential regulator of the pathogenesis of several diseases, including cancer and neurological disorders. Therefore, APE1 inhibitors have therapeutic potential. APE1 is highly expressed in the central nervous system (CNS) and participates in tissue homeostasis, and its roles in neurodegenerative and neuroinflammatory diseases have been elucidated. This review discusses known roles of APE1 in innate and adaptive immunity, especially in the CNS, recent evidence of a role in the extracellular environment, and the therapeutic potential of APE1 inhibitors in infectious/immune diseases.

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Section: Ape1 In Adaptive Immunitymentioning

confidence: 99%

APE1/Ref-1 Role in Inflammation and Immune Response

et al. 2022

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“…Monofunctional DNA glycosylases, such as alkyl adenine DNA glycosylase or uracil DNA glycosylase, create abasic sites, while bifunctional DNA glycosylases, such as 8-oxoguanine DNA glycosylase (OGG1), NEIL1−3, additionally cleave the 3′ site on the abasic sugar [ 21 , 22 ]. The excision of the damaged base initiates the repair process, where the excision site is recognized by apurinic/apyrimidinic endonuclease (APE) [ 23 ]. If monofunctional DNA glycosylase acts on the damaged nucleotide, APE1 cleaves the site, while after bifunctional glycosylase, APE2 is the endonuclease responsible for the cleavage [ 23 ].…”

Section: The Dna Damage Responsementioning

confidence: 99%

“…The excision of the damaged base initiates the repair process, where the excision site is recognized by apurinic/apyrimidinic endonuclease (APE) [ 23 ]. If monofunctional DNA glycosylase acts on the damaged nucleotide, APE1 cleaves the site, while after bifunctional glycosylase, APE2 is the endonuclease responsible for the cleavage [ 23 ]. Replacement of the damaged/missing nucleotide is filled by the action of polymerase β or, if the gap is bigger than one nucleotide, with polymerase δ or ε.…”

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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“…APE2 (Apurinic/apyrimidinic endonuclease-2, also known as APEX2 or APN2) is an evolutionarily conserved protein with strong 3′-phosphodiesterase and 3′-5′ exonuclease activities but weak AP endonuclease activity and has been implicated in genome and epigenome integrity maintenance ( Burkovics et al, 2009 ; Chaudhari et al, 2021 ; Lin et al, 2021 ). Prior studies using different model systems have shown that APE2 plays crucial roles in DNA repair pathways including the base excision repair (BER) pathway, SSB repair pathway, DSB generation and DSB repair pathway, DDR pathways including the ATR-Chk1 DDR pathway and p53-dependent DDR pathway, immune responses including immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR), and active DNA demethylation ( Unk et al, 2001 ; Burkovics et al, 2006 , 2009 ; Guikema et al, 2007 ; Dan et al, 2008 ; Sabouri et al, 2009 ; Willis et al, 2013 ; Li et al, 2018 ; Lin et al, 2018 , 2020 ; Cupello et al, 2019 ; Yan, 2019 ; Alvarez-Quilon et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

Hossain

Lin

Driscoll

et al. 2021

Front. Cell Dev. Biol.

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The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

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Apurinic/Apyrimidinic Endonuclease 2 (APE2): An ancillary enzyme for contextual base excision repair mechanisms to preserve genome stability

Cited by 8 publications

References 158 publications

APE1/Ref-1 Role in Inflammation and Immune Response

APE1/Ref-1 Role in Inflammation and Immune Response

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

APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

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