Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Molecular cell, 2022-10, Vol.82 (20), p.3794-3809.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. [Display omitted] •Calcineurin activates Top2B and induces it to form DSBs in response to NMDAR activity•Calcineurin dephosphorylates Top2B at residues S1509 and S1511 within its C-terminal•Calcineurin-mediated DSBs regulate the expression of neuronal early response genes•Neuronal-activity-induced DSB sites preferentially localize to the nuclear periphery Here, we report that neuronal stimulation triggers the phosphatase calcineurin to dephosphorylate the topoisomerase Top2B and induce it to form DNA breaks within the promoters of neuronal early response genes, which, in turn, promotes their rapid transcription. We further show that these events are compartmentalized at the nuclear periphery.