Chemical Inhibition of Apurinic-Apyrimidinic Endonuclease 1 Redox and DNA Repair Functions Affects the Inflammatory Response via Different but Overlapping Mechanisms

Oliveira, Thais Teixeira; Fontes-Dantas, Fabrícia Lima; Oliveira, Rayssa Karla de Medeiros; Pinheiro, Daniele Maria Lopes; Coutinho, Leonam Gomes; Silva, Vandeclécio Lira da; Souza, Sandro J. de; Agnez-Lima, Lucymara Fassarella

doi:10.3389/fcell.2021.731588

Cited by 7 publications

(11 citation statements)

References 92 publications

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“…APE1 plays multiple roles in immune responses, including ROS regulation and cytokine expression in cells mediating innate immunity, including monocytes ( 34 ), macrophages ( 19 ), keratinocytes ( 18 ), dendritic cells ( 7 ), neurons ( 94 , 95 , 97 , 99 ), and astrocytes ( 105 ), and regulation of B cell activation and CSR in adaptive immunity ( 112 ). Despite its role in cytokine expression, it is still necessary to determine whether this regulatory control extends to all cell types or is cell type-specific.…”

Section: Discussionmentioning

confidence: 99%

“…ELK1 expression is regulated by ERK pathway, EGR1, and TET enzymes ( 82 – 84 ). In this context, our findings suggest that both redox and DNA repair activities of APE1 regulate ELK1 expression through independent but overlapping mechanisms ( 34 ). Together, these data suggest a role of DNA repair in regulating gene expression, influencing the expression of inflammatory mediators.…”

Section: Ape1 In Innate Immunitymentioning

confidence: 90%

“…In general, the studies cited above describe the associations of APE1 redox function or reduced APE1 expression with inflammatory regulation. However, our group recently showed that inhibition of AP site repair by methoxyamine inhibits the expression of IL-8, IL-6, TNFα, IL-10, and MCP1 in LPS-induced U937 cells ( 34 ). This treatment also decreased expression of genes involved in prostaglandin biosynthesis and MyD88-independent toll-like receptor signaling pathway genes.…”

Section: Ape1 In Innate Immunitymentioning

confidence: 99%

“…MX has been studied in clinical trials for the treatment of solid tumors and lymphoma (NCT01851369). Although MX decreased the expression of LPS-induced cytokines and negatively regulated genes involved in prostaglandin production in monocytes ( 34 ), the role of MX in inflammatory disorders requires further exploration. Similarly, lucanthone inhibits DNA repair activity of APE1 without affecting the redox function ( 39 ) and is in phase II clinical trials for treatment of brain metastases secondary to non-small cell lung cancer (NCT02014545).…”

Section: Ape1 Inhibitors and Potential Therapeutic Drugsmentioning

confidence: 99%

“…Thus, the endonuclease activity of APE1 is also involved in regulating chromatin and gene expression (24)(25)(26)(27) [reviewed in (32)]. Thus, some genes, including VEGF, and cytokines, are regulated by the redox and repair functions of APE1 (33,34).…”

Section: Introduction Ape1 -From Structure To Functionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Ape1 In Innate Immunitymentioning

confidence: 90%

Section: Ape1 In Innate Immunitymentioning

confidence: 99%

Section: Ape1 Inhibitors and Potential Therapeutic Drugsmentioning

confidence: 99%

Section: Introduction Ape1 -From Structure To Functionmentioning

confidence: 99%

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APE1/Ref-1 Role in Inflammation and Immune Response

et al. 2022

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APEX1 Nuclease and Redox Functions are Both Essential for Adult Mouse Hematopoietic Stem and Progenitor Cells

Zaunz

Smedt

Lauwereins

et al. 2023

Stem Cell Rev and Rep

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Self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) are carefully controlled by extrinsic and intrinsic factors, to ensure the lifelong process of hematopoiesis. Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein implicated in DNA repair and transcriptional regulation. Although previous studies have emphasized the necessity of studying APEX1 in a lineage-specific context and its role in progenitor differentiation, no studies have assessed the role of APEX1, nor its two enzymatic domains, in supporting adult HSPC function. In this study, we demonstrated that complete loss of APEX1 from murine bone marrow HSPCs (induced by CRISPR/Cas9) caused severe hematopoietic failure following transplantation, as well as a HSPC expansion defect in culture conditions maintaining in vivo HSC functionality. Using specific inhibitors against either the nuclease or redox domains of APEX1 in combination with single cell transcriptomics (CITE-seq), we found that both APEX1 nuclease and redox domains are regulating mouse HSPCs, but through distinct underlying transcriptional changes. Inhibition of the APEX1 nuclease function resulted in loss of HSPCs accompanied by early activation of differentiation programs and enhanced lineage commitment. By contrast, inhibition of the APEX1 redox function significantly downregulated interferon-stimulated genes and regulons in expanding HSPCs and their progeny, resulting in dysfunctional megakaryocyte-biased HSPCs, as well as loss of monocytes and lymphoid progenitor cells. In conclusion, we demonstrate that APEX1 is a key regulator for adult regenerative hematopoiesis, and that the APEX1 nuclease and redox domains differently impact proliferating HSPCs. Graphical Abstract

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