Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination

Barbara Frossi, Giulia Antoniali, Kefei Yu, Nahid Akhtar, Mark Kaplan, Mark Kelley, Gianluca Tell, Carlo E.M. Pucillo

Research output: Contribution to journalArticle

2 Citations (Scopus)

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-B 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.

Original languageEnglish (US)
Pages (from-to)5198-5207
Number of pages10
JournalJournal of Biological Chemistry
Volume294
Issue number13
DOIs
StatePublished - Jan 1 2019

Fingerprint

DNA-(Apurinic or Apyrimidinic Site) Lyase
Endonucleases
Human Activities
Immunoglobulin A
Genetic Recombination
Oxidation-Reduction
Switches
Repair
DNA Repair
Cells
Cell Line
Regulator Genes
DNA
Gene expression
Interleukin-6
B-Lymphocytes
Transcription Factors
Inflammation
Gene Expression
Antigens

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination. / Frossi, Barbara; Antoniali, Giulia; Yu, Kefei; Akhtar, Nahid; Kaplan, Mark; Kelley, Mark; Tell, Gianluca; Pucillo, Carlo E.M.

In: Journal of Biological Chemistry, Vol. 294, No. 13, 01.01.2019, p. 5198-5207.

Research output: Contribution to journalArticle

Frossi, Barbara ; Antoniali, Giulia ; Yu, Kefei ; Akhtar, Nahid ; Kaplan, Mark ; Kelley, Mark ; Tell, Gianluca ; Pucillo, Carlo E.M. / Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 13. pp. 5198-5207.
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