TY - JOUR
T1 - Calcineurin dephosphorylates topoisomerase IIβ and regulates the formation of neuronal-activity-induced DNA breaks
AU - Delint-Ramirez, Ilse
AU - Konada, Lahiri
AU - Heady, Lance
AU - Rueda, Richard
AU - Jacome, Alvaro Sebastian Vaca
AU - Marlin, Eric
AU - Marchioni, Charlotte
AU - Segev, Amir
AU - Kritskiy, Oleg
AU - Yamakawa, Satoko
AU - Reiter, Andrew H.
AU - Tsai, Li Huei
AU - Madabhushi, Ram
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/10/20
Y1 - 2022/10/20
N2 - 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.
AB - 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.
KW - Top2B
KW - activity-induced DNA breaks
KW - calcineurin
KW - early response genes
KW - nuclear periphery
UR - http://www.scopus.com/inward/record.url?scp=85140417797&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85140417797&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2022.09.012
DO - 10.1016/j.molcel.2022.09.012
M3 - Article
C2 - 36206766
AN - SCOPUS:85140417797
SN - 1097-2765
VL - 82
SP - 3794-3809.e8
JO - Molecular cell
JF - Molecular cell
IS - 20
ER -