Topoisomerase I inhibition and peripheral nerve injury induce DNA breaks and ATF3-associated axon regeneration in sensory neurons.

Abstract

Although axonal damage induces rapid changes in gene expression in primary sensory neurons, it remains unclear how this process is initiated. The transcription factor ATF3, one of the earliest genes responding to nerve injury, regulates expression of downstream genes that enable axon regeneration. By exploiting ATF3 reporter systems, we identify topoisomerase inhibitors as ATF3 inducers, including camptothecin. Camptothecin increases ATF3 expression and promotes neurite outgrowth in sensory neurons in vitro and enhances axonal regeneration after sciatic nerve crush in vivo. Given the action of topoisomerases in producing DNA breaks, we determine that they do occur immediately after nerve damage at the ATF3 gene locus in injured sensory neurons and are further increased after camptothecin exposure. Formation of DNA breaks in injured sensory neurons and enhancement of it pharmacologically may contribute to the initiation of those transcriptional changes required for peripheral nerve regeneration.

• Authors: Yung-Chih Cheng, Andrew Snavely, Lee B Barrett, Xuefei Zhang, Crystal Herman, Devlin J Frost, Priscilla Riva, Ivan Tochitsky, Riki Kawaguchi, Bhagat Singh, Jelena Ivanis, Eric A Huebner, Anthony Arvanites, Vatsal Oza, Lance Davidow, Rie Maeda, Miyuki Sakuma, Alyssa Grantham, Qing Wang, Amelia N Chang, Kathleen Pfaff, Michael Costigan, Giovanni Coppola, Lee L Rubin, Bjoern Schwer, Frederick W Alt, Clifford J Woolf
• Journal: Cell reports (Cell Rep) Vol. 36 Issue 10 Pg. 109666 (09 07 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34496254 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Activating Transcription Factor 3
• Atf3 protein, mouse
• DNA Topoisomerases, Type I

Topics

• Activating Transcription Factor 3 (metabolism)
• Animals
• Axons (metabolism)
• DNA Breaks (drug effects)
• DNA Topoisomerases, Type I (drug effects, metabolism)
• Gene Expression (physiology)
• Mice, Inbred C57BL
• Nerve Regeneration (drug effects, physiology)
• Neuronal Outgrowth (physiology)
• Peripheral Nerve Injuries (metabolism)
• Sciatic Nerve (metabolism)
• Sensory Receptor Cells (metabolism)