Calcineurin dephosphorylates topoisomerase IIβ and regulates the formation of neuronal-activity-induced DNA breaks

Ilse Delint-Ramirez, Lahiri Konada, Lance Heady, Richard Rueda, Alvaro Sebastian Vaca Jacome, Eric Marlin, Charlotte Marchioni, Amir Segev, Oleg Kritskiy, Satoko Yamakawa, Andrew H. Reiter, Li Huei Tsai, Ram Madabhushi

Research output: Contribution to journalArticlepeer-review

Abstract

Neuronal activity induces topoisomerase IIβ (Top2B) to generate DNA double-strand breaks (DSBs) within the promoters of neuronal early response genes (ERGs) and facilitate their transcription, and yet, the mechanisms that control Top2B-mediated DSB formation are unknown. Here, we report that stimulus-dependent calcium influx through NMDA receptors activates the phosphatase calcineurin to dephosphorylate Top2B at residues S1509 and S1511, which stimulates its DNA cleavage activity and induces it to form DSBs. Exposing mice to a fear conditioning paradigm also triggers Top2B dephosphorylation at S1509 and S1511 in the hippocampus, indicating that calcineurin also regulates Top2B-mediated DSB formation following physiological neuronal activity. Furthermore, calcineurin-Top2B interactions following neuronal activity and sites that incur activity-induced DSBs are preferentially localized at the nuclear periphery in neurons. Together, these results reveal how radial gene positioning and the compartmentalization of activity-dependent signaling govern the position and timing of activity-induced DSBs and regulate gene expression patterns in neurons.

Original languageEnglish (US)
Pages (from-to)3794-3809
Number of pages16
JournalMolecular cell
Volume82
Issue number20
DOIs
StatePublished - Oct 20 2022

Keywords

  • activity-induced DNA breaks
  • calcineurin
  • early response genes
  • nuclear periphery
  • Top2B

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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