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The double-edged sword of the double-stranded break

Neuropsychopharmacology (2022)Cite this article

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Neurons, terminally differentiated post-mitotic cells, face a remarkable challenge: throughout life, they must maintain a gene expression program that defines cellular identity while simultaneously allowing for transcriptional plasticity in response to a changing environment. There is robust literature demonstrating that neurons initiate a transcriptional response to neuronal activity within minutes, leading to the expression of immediate early genes (IEGs), including Fos, Arc, Jun, and Npas4. Subsequently, IEGs lead to the expression of more cell-type specific late response genes, such as Bdnf, Igf1, Homer1, Dnmt3a, Hdac5, and Kdm1a, which are diverse and less well characterized [1]. Neurons also stably retain information through epigenetic mechanisms, including histone modifications and molecular changes to DNA itself, either through DNA methylation and hydroxymethylation or other more recently discovered epigenetic modifications [2].

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Fig. 1: Neurons produce double-stranded DNA breaks (DSBs) in response to activity.

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Funding

RJF is funded through the HMS Broderick Phytocannabinoid Research grant. JS is funded through R01MH108665 and R01MH123993.

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Authors and Affiliations

  1. Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA

    Robert J. Fenster & Junghyup Suh

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Robert J. Fenster & Junghyup Suh

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  1. Robert J. Fenster
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  2. Junghyup Suh
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RJF conceived of the topic for this article; RJF and JS co-wrote the article; and JS produced the figure.

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Correspondence to Robert J. Fenster.

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The authors declare no competing interests.

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Fenster, R.J., Suh, J. The double-edged sword of the double-stranded break. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01403-4

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  • DOI: https://doi.org/10.1038/s41386-022-01403-4

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