Cheng YC, Snavely A, Barrett LB, Zhang X, Herman C, Frost DJ, Riva P, Tochitsky I, Kawaguchi R, Singh B, Ivanis J, Huebner EA, Arvanites A, Oza V, Davidow L, Maeda R, Sakuma M, Grantham A, Wang Q, Chang AN, Pfaff K, Costigan M, Coppola G, Rubin LL, Schwer B, Alt FW, Woolf CJ. 2021. Topoisomerase I inhibition and peripheral nerve injury induce DNA breaks and ATF3-associated axon regeneration in sensory neurons. Cell reports. 36(10):109666. Pubmed: 34496254 DOI:S2211-1247(21)01110-4


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.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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Lee Rubin investigates the key molecular mediators of different neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.

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