Parp1 promotes sleep, which enhances DNA repair in neurons

David Zada; Yaniv Sela; Noa Matosevich; Adir Monsonego; Tali Lerer-Goldshtein; Yuval Nir; Lior Appelbaum

doi:10.1016/j.molcel.2021.10.026

Parp1 promotes sleep, which enhances DNA repair in neurons

David Zada, Yaniv Sela, Noa Matosevich, Adir Monsonego, Tali Lerer-Goldshtein, Yuval Nir, Lior Appelbaum

Tel Aviv University

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsal pallium. Induction of DNA damage by neuronal activity and mutagens triggered sleep and DNA repair. The activity of the DNA damage response (DDR) proteins Rad52 and Ku80 increased during sleep, and chromosome dynamics enhanced Rad52 activity. The activity of the DDR initiator poly(ADP-ribose) polymerase 1 (Parp1) increased following sleep deprivation. In both larva zebrafish and adult mice, Parp1 promoted sleep. Inhibition of Parp1 activity reduced sleep-dependent chromosome dynamics and repair. These results demonstrate that DNA damage is a homeostatic driver for sleep, and Parp1 pathways can sense this cellular pressure and facilitate sleep and repair activity.

Original language	English
Pages (from-to)	4979-4993.e7
Journal	Molecular Cell
Volume	81
Issue number	24
DOIs	https://doi.org/10.1016/j.molcel.2021.10.026
State	Published - 16 Dec 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Funding

The Appelbaum lab is supported by the Israel Science Foundation (ISF, grant no. 961/19 ), the United States–Israel Binational Science Foundation (BSF, grant no. 2017105 ), the National Science Foundation (NSF)–BSF joint funding EDGE program (NSF-BSF grant no. 2019604), and the National Institute of Health (NIH, R01 MH116470 ). Research in the Nir lab is supported by ISF grants 1326/15 and 51/11 (I-CORE Cognitive Sciences), the Adelis Foundation , the European Research Council ( ERC-2019-CoG 864353 ), and by an Azrieli Foundation fellowship award (to Y.S.). We thank Ann Avron and Yael Laure for assistance in editing the manuscript; Dr. Noa Alon for assistance in designing the schematic illustrations; Dr. Alona Zilberberg, Dr. Sally Shpunigin, and the members of the Appelbaum lab for technical assistance; and Dr. Noa Regev, Itai Caspit, Arielle Lavi, and Talia Engel for assistance with mouse experiments and sleep scoring.

Funders	Funder number
NSF-BSF	2019604
National Science Foundation
National Institutes of Health	1326/15
National Institute of Mental Health	R01MH116470
Achelis Foundation
European Commission	ERC-2019-CoG 864353
United States-Israel Binational Science Foundation	2017105
Israel Science Foundation	961/19
Azrieli Foundation

Keywords

DNA damage response
Ku80
NREM
Parp1
Rad52
chromosome dynamics
homeostasis
mice
sleep
zebrafish

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10.1016/j.molcel.2021.10.026

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title = "Parp1 promotes sleep, which enhances DNA repair in neurons",

abstract = "The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsal pallium. Induction of DNA damage by neuronal activity and mutagens triggered sleep and DNA repair. The activity of the DNA damage response (DDR) proteins Rad52 and Ku80 increased during sleep, and chromosome dynamics enhanced Rad52 activity. The activity of the DDR initiator poly(ADP-ribose) polymerase 1 (Parp1) increased following sleep deprivation. In both larva zebrafish and adult mice, Parp1 promoted sleep. Inhibition of Parp1 activity reduced sleep-dependent chromosome dynamics and repair. These results demonstrate that DNA damage is a homeostatic driver for sleep, and Parp1 pathways can sense this cellular pressure and facilitate sleep and repair activity.",

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AB - The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsal pallium. Induction of DNA damage by neuronal activity and mutagens triggered sleep and DNA repair. The activity of the DNA damage response (DDR) proteins Rad52 and Ku80 increased during sleep, and chromosome dynamics enhanced Rad52 activity. The activity of the DDR initiator poly(ADP-ribose) polymerase 1 (Parp1) increased following sleep deprivation. In both larva zebrafish and adult mice, Parp1 promoted sleep. Inhibition of Parp1 activity reduced sleep-dependent chromosome dynamics and repair. These results demonstrate that DNA damage is a homeostatic driver for sleep, and Parp1 pathways can sense this cellular pressure and facilitate sleep and repair activity.

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Parp1 promotes sleep, which enhances DNA repair in neurons

Abstract

Bibliographical note

Funding

Keywords

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