Abstract
The 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.
Highlights
The base excision repair (BER) pathway is an important DNA repair pathway and is essential for immune responses
apyrimidinic endonuclease 1 (APE1) endonuclease activity is important for class switch recombination (CSR), it is dispensable for somatic hypermutation (SHM) and activation-induced cytidine deaminase (AID)-induced DNA breaks and may function as a DNA end-processing enzyme to facilitate the joining of broken ends during CSR [5]
Despite several uracil glycosylases being present in mammals, APE1 is the only AP-endonuclease, a weak endonuclease activity has been recently identified for APE2 [16, 34, 35]
Summary
The base excision repair (BER) pathway is an important DNA repair pathway and is essential for immune responses. Downstream consequences of transduced signals are the initiating of genomic rearrangement that induces somatic hypermutation (SHM)4 [1] and a class switch recombination (CSR) that switches the CH region [1] Both immunoglobulin SHM and CSR are essential mechanisms for the generation of a highaffinity, adaptive humoral immune response; require transcription; and are dependent on the activation-induced cytidine deaminase (AID), which converts cytosine to uracil and contributes to the formation of requisite single-stranded DNA substrates. The abbreviations used are: SHM, somatic hypermutation; APE1, apurinic/ apyrimidinic endonuclease 1; AID, activation-induced cytidine deaminase; BER, base excision repair; CSR, class switch recombination; IL, interleukin; IR, ionizing radiation; PI, propidium iodide; STAT, signal transducers and activators of transcription; TGF, transforming growth factor. And for the first time, we provide evidence that the redox function of the protein plays an important role in regulating CSR through the IL-6 signaling pathway and proper IgA expression
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