Frossi, BarbaraAntoniali, GiuliaYu, KefeiAkhtar, NahidKaplan, Mark H.Kelley, Mark R.Tell, GianlucaPucillo, Carlo E.2022-04-122022-04-122019-03-29Frossi B, Antoniali G, Yu K, Akhtar N, Kaplan MH, Kelley MR, Tell G, Pucillo CEM. Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination. J Biol Chem. 2019 Mar 29;294(13):5198-5207. doi: 10.1074/jbc.RA118.006601. Epub 2019 Jan 31. PMID: 30705092; PMCID: PMC6442068.https://hdl.handle.net/1805/28483The base excision repair (BER) pathway is an important DNA repair pathway and is essential for immune responses. In fact, it regulates both the antigen-stimulated somatic hypermutation (SHM) process and plays a central function in the process of class switch recombination (CSR). For both processes, a central role for apurinic/apyrimidinic endonuclease 1 (APE1) has been demonstrated. APE1 acts also as a master regulator of gene expression through its redox activity. APE1's redox activity stimulates the DNA-binding activity of several transcription factors, including NF-κB and a few others involved in inflammation and in immune responses. Therefore, it is possible that APE1 has a role in regulating the CSR through its function as a redox coactivator. The present study was undertaken to address this question. Using the CSR-competent mouse B-cell line CH12F3 and a combination of specific inhibitors of APE1's redox (APX3330) and repair (compound 3) activities, APE1-deficient or -reconstituted cell lines expressing redox-deficient or endonuclease-deficient proteins, and APX3330-treated mice, we determined the contributions of both endonuclease and redox functions of APE1 in CSR. We found that APE1's endonuclease activity is essential for IgA-class switch recombination. We provide evidence that the redox function of APE1 appears to play a role in regulating CSR through the interleukin-6 signaling pathway and in proper IgA expression. Our results shed light on APE1's redox function in the control of cancer growth through modulation of the IgA CSR process.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalBase excision repair (BER)DNA endonucleaseDNA transcriptionClass switch recombinationRedox-inhibitorArticle