Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The threat of programmed DNA damage to neuronal genome integrity and plasticity

Nature Genetics volume 54, pages 115–120 (2022)Cite this article

Subjects

Abstract

The neuronal genome is particularly sensitive to loss or attenuation of DNA repair, and many neurological diseases ensue when DNA repair is impaired. It is well-established that the neuronal genome is subjected to stochastic DNA damage, most likely because of extensive oxidative stress in the brain. However, recent studies have identified unexpected high levels of ‘programmed’ DNA breakage in neurons, which we propose arise during physiological DNA metabolic processes intrinsic to neuronal development, differentiation and maintenance. The role of programmed DNA breaks in normal neuronal physiology and disease remains relatively unexplored thus far. However, bulk and single-cell sequencing analyses of neurodegenerative diseases have revealed age-related somatic mutational signatures that are enriched in regulatory regions of the genome. Here, we explore a paradigm of DNA repair in neurons, in which the genome is safeguarded from erroneous impacts of programmed genome breakage intrinsic to normal neuronal function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ‘Programmed’ DNA damage by topoisomerases.
Fig. 2: ‘Programmed’ BER-mediated cytosine demethylation.
Fig. 3: Programmed DNA damage as source of neuropathology.

Similar content being viewed by others

References

  1. Caldecott, K. W. Single-strand break repair and genetic disease. Nat. Rev. Genet. 9, 619–631 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McKinnon, P. J. & Caldecott, K. W. DNA strand break repair and human genetic disease. Annu. Rev. Genomics Hum. Genet. 8, 37–55 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Tiwari, V. & Wilson, D. M. III. DNA damage and associated DNA repair defects in disease and premature aging. Am. J. Hum. Genet. 105, 237–257 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McKinnon, P. J. Genome integrity and disease prevention in the nervous system. Genes Dev. 31, 1180–1194 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Canela, A. et al. Genome organization drives chromosome fragility. Cell 170, 507–521 e518 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gomez-Herreros, F. DNA double strand breaks and chromosomal translocations induced by DNA topoisomerase II. Front. Mol. Biosci. 6, 141 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pourquier, P. & Pommier, Y. Topoisomerase I-mediated DNA damage. Adv. Cancer Res. 80, 189–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Pommier, Y. et al. Repair of topoisomerase I-mediated DNA damage. Prog. Nucleic Acid Res. Mol. Biol. 81, 179–229 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zagnoli-Vieira, G. & Caldecott, K. W. Untangling trapped topoisomerases with tyrosyl-DNA phosphodiesterases. DNA Repair (Amst.) 94, 102900 (2020).

    Article  CAS  Google Scholar 

  12. El-Khamisy, S. F. et al. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434, 108–113 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Takashima, H. et al. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat. Genet. 32, 267–272 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Gomez-Herreros, F. et al. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat. Genet. 46, 516–521 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Zagnoli-Vieira, G. et al. Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurol. Genet. 4, e262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hoch, N. C. et al. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541, 87–91 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. O’Connor, E. et al. Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy. J. Neurol. Neurosurg. Psychiatry 89, 1230–1232 (2018).

    Article  PubMed  Google Scholar 

  18. Kalasova, I. et al. Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair. Nucleic Acids Res. 48, 6672–6684 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Reynolds, J. J., Walker, A. K., Gilmore, E. C., Walsh, C. A. & Caldecott, K. W. Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair. Nucleic Acids Res. 40, 6608–6619 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shen, J. et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat. Genet. 42, 245–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Alvarez-Quilon, A. et al. ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nat. Commun. 5, 3347 (2014).

    Article  PubMed  Google Scholar 

  22. Katyal, S. et al. Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat. Neurosci. 17, 813–821 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Hoa, N. N. et al. Mre11 is essential for the removal of lethal topoisomerase 2 covalent cleavage complexes. Mol. Cell 64, 1010 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Stewart, G. S. et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577–587 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. King, I. F. et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Iyama, T. & Wilson, D. M. III. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst.) 12, 620–636 (2013).

  29. Imai, K. et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat. Immunol. 4, 1023–1028 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Rada, C. et al. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12, 1748–1755 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Saha, T., Sundaravinayagam, D. & Di Virgilio, M. Charting a DNA repair roadmap for immunoglobulin class switch recombination. Trends Biochem. Sci. 46, 184–199 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Nussenzweig, A. & Nussenzweig, M. C. Origin of chromosomal translocations in lymphoid cancer. Cell 141, 27–38 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Maiti, A. & Drohat, A. C. Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J. Biol. Chem. 286, 35334–35338 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu, X. & Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Reid, D. A. et al. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons. Science 372, 91–94 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Wu, W. et al. Neuronal enhancers are hotspots for DNA single-strand break repair. Nature 593, 440–444 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Caldecott, K. W. Mammalian DNA base excision repair: dancing in the moonlight. DNA Repair (Amst.) 93, 102921 (2020).

    Article  CAS  Google Scholar 

  42. Ahel, I. et al. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443, 713–716 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Demin, A. A. et al. XRCC1 prevents toxic PARP1 trapping during DNA base excision repair. Mol. Cell 81, 3018–3030 e3015 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Caldecott, K. W. XRCC1 protein; form and function. DNA Repair (Amst.) 81, 102664 (2019).

    Article  CAS  Google Scholar 

  45. Mol, C. D., Izumi, T., Mitra, S. & Tainer, J. A. DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected]. Nature 403, 451–456 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Wilson, S. H. & Kunkel, T. A. Passing the baton in base excision repair. Nat. Struct. Biol. 7, 176–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Frosina, G. et al. Two pathways for base excision repair in mammalian cells. J. Biol. Chem. 271, 9573–9578 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Kubota, Y. et al. Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. EMBO J. 15, 6662–6670 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, Y. E. et al. An atlas of gene regulatory elements in adult mouse cerebrum. Nature 598, 129–136 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, H. et al. DNA methylation atlas of the mouse brain at single-cell resolution. Nature 598, 120–128 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu, Z. J., Martinez Cuesta, S., van Delft, P. & Balasubramanian, S. Sequencing abasic sites in DNA at single-nucleotide resolution. Nat. Chem. 11, 629–637 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Roychoudhury, S. et al. Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome. Proc. Natl Acad. Sci. USA 117, 11409–11420 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Poetsch, A. R., Boulton, S. J. & Luscombe, N. M. Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis. Genome Biol. 19, 215 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Amente, S. et al. Genome-wide mapping of 8-oxo-7,8-dihydro-2ʹ-deoxyguanosine reveals accumulation of oxidatively-generated damage at DNA replication origins within transcribed long genes of mammalian cells. Nucleic Acids Res. 47, 221–236 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Ding, Y., Fleming, A. M. & Burrows, C. J. Sequencing the mouse genome for the oxidatively modified base 8-oxo-7,8-dihydroguanine by OG-Seq. J. Am. Chem. Soc. 139, 2569–2572 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hu, J., Adar, S., Selby, C. P., Lieb, J. D. & Sancar, A. Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution. Genes Dev. 29, 948–960 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lio, C. J. et al. TET methylcytosine oxidases: new insights from a decade of research. J. Biosci. 45, 21 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Steinacher, R. et al. SUMOylation coordinates BERosome assembly in active DNA demethylation during cell differentiation. EMBO J. https://doi.org/10.15252/embj.201899242 (2019).

  60. Adamowicz, M. et al. XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair. Nat. Cell Biol. https://doi.org/10.1038/s41556-021-00792-w (2021).

  61. Mao, K. & Zhang, G. The role of PARP1 in neurodegenerative diseases and aging. FEBS J. https://doi.org/10.1111/febs.15716 (2021).

  62. Komulainen, E. et al. Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures. EMBO Rep. 22, e51851 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Miller, M. B., Reed, H. C. & Walsh, C. A. Brain somatic mutation in aging and Alzheimer’s disease. Annu. Rev. Genomics Hum. Genet. https://doi.org/10.1146/annurev-genom-121520-081242 (2021).

  64. Cho, J. E. & Jinks-Robertson, S. Deletions associated with stabilization of the Top1 cleavage complex in yeast are products of the nonhomologous end-joining pathway. Proc. Natl Acad. Sci. USA 116, 22683–22691 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Stantial, N. et al. Trapped topoisomerase II initiates formation of de novo duplications via the nonhomologous end-joining pathway in yeast. Proc. Natl Acad. Sci. USA 117, 26876–26884 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gomez-Herreros, F. et al. TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription. Nat. Commun. 8, 233 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Canela, A. et al. Topoisomerase II-induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity. Mol. Cell 75, 252–266 e258 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).

    Article  CAS  PubMed  Google Scholar 

  69. Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sanders, M. A. et al. Life without mismatch repair. Preprint at bioRxiv https://doi.org/10.1101/2021.04.14.437578 (2021).

  73. Fang, H. et al. Deficiency of replication-independent DNA mismatch repair drives a 5-methylcytosine deamination mutational signature in cancer. Sci. Adv. 7, eabg4398 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shen, J. C., Rideout, W. M. III & Jones, P. A. The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res 22, 972–976 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gibbs, P. E., McDonald, J., Woodgate, R. & Lawrence, C. W. The relative roles in vivo of Saccharomyces cerevisiae Pol eta, Pol zeta, Rev1 protein and Pol32 in the bypass and mutation induction of an abasic site, T-T (6-4) photoadduct and T-T cis-syn cyclobutane dimer. Genetics 169, 575–582 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zlatanou, A. et al. The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol eta in response to oxidative DNA damage in human cells. Mol. Cell 43, 649–662 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Pena-Diaz, J. et al. Noncanonical mismatch repair as a source of genomic instability in human cells. Mol. Cell 67, 162 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Schanz, S., Castor, D., Fischer, F. & Jiricny, J. Interference of mismatch and base excision repair during the processing of adjacent U/G mispairs may play a key role in somatic hypermutation. Proc. Natl Acad. Sci. USA 106, 5593–5598 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Grin, I. & Ishchenko, A. A. An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation. Nucleic Acids Res. 44, 3713–3727 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lindahl, T. & Nyberg, B. Rate of depurination of native deoxyribonucleic acid. Biochemistry 11, 3610–3618 (1972).

    Article  CAS  PubMed  Google Scholar 

  81. Swain, U. & Subba Rao, K. Study of DNA damage via the comet assay and base excision repair activities in rat brain neurons and astrocytes during aging. Mech. Ageing Dev. 132, 374–381 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Caldecott, K. W. DNA single-strand break repair. Exp. Cell. Res. 329, 2–8 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Dong, X. et al. Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease. Nat. Neurosci. 21, 1482–1492 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Eckart, N. et al. Functional characterization of schizophrenia-associated variation in CACNA1C. PLoS ONE 11, e0157086 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Fabbri, C. & Serretti, A. Role of 108 schizophrenia-associated loci in modulating psychopathological dimensions in schizophrenia and bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 174, 757–764 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Song, M. et al. Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes. Nat. Genet. 51, 1252–1262 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rodin, R. E. et al. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat. Neurosci. 24, 176–185 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chapuis, J. et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol. Psychiatry 18, 1225–1234 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Sanchez-Mut, J. V. et al. PM20D1 is a quantitative trait locus associated with Alzheimer’s disease. Nat. Med. 24, 598–603 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Soldner, F. et al. Parkinson-associated risk variant in distal enhancer of ɑ-synuclein modulates target gene expression. Nature 533, 95–99 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nott, A. et al. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science 366, 1134–1139 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chun, H. et al. Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2− production. Nat. Neurosci. 23, 1555–1566 (2020).

    Article  CAS  PubMed  Google Scholar 

  94. Gabbita, S. P., Lovell, M. A. & Markesbery, W. R. Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J. Neurochem. 71, 2034–2040 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Lyras, L., Cairns, N. J., Jenner, A., Jenner, P. & Halliwell, B. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J. Neurochem. 68, 2061–2069 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Mecocci, P., MacGarvey, U. & Beal, M. F. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 36, 747–751 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Shanbhag, N. M. et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol. Commun. 7, 77 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Park, J. S. et al. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nat. Commun. 10, 3090 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Rudenko, A. et al. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109–1122 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kaas, G. A. et al. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79, 1086–1093 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Yu, H. et al. Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nat. Neurosci. 18, 836–843 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Antunes, C. et al. Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice. Mol. Psychiatry 26, 1445–1457 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Suberbielle, E. et al. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat. Neurosci. 16, 613–621 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Madabhushi, R. et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161, 1592–1605 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Stott, R. T., Kritsky, O. & Tsai, L. H. Profiling DNA break sites and transcriptional changes in response to contextual fear learning. PLoS ONE 16, e0249691 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Crowe, S. L., Tsukerman, S., Gale, K., Jorgensen, T. J. & Kondratyev, A. D. Phosphorylation of histone H2A.X as an early marker of neuronal endangerment following seizures in the adult rat brain. J. Neurosci. 31, 7648–7656 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wei, P. C. et al. Long neural genes harbor recurrent DNA break clusters in neural stem/progenitor cells. Cell 164, 644–655 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

K.W.C. is supported by Programme Grants from the UK Medical Research Council (grant no. MR/P010121/1), Cancer Research UK (grant no. C6563/A7322) and by ERC Advanced Investigator (SIDSCA grant no. 694996) and Royal Society Wolfson Research Merit Awards. The M.E.W. laboratory is supported by the NINDS Intramural Research Program. The A.N. laboratory is supported by the Intramural Research Program of the NIH, an Ellison Medical Foundation Senior Scholar in Aging Award (grant no. AG-SS-2633-11), the Department of Defense Awards (grant nos. W81XWH-16-1-599 and W81XWH-19-1-0652), the Alex’s Lemonade Stand Foundation Award and an NIH Intramural FLEX Award.

Author information

Authors and Affiliations

  1. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK

    Keith W. Caldecott

  2. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA

    Michael E. Ward

  3. Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA

    André Nussenzweig

Authors
  1. Keith W. Caldecott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. André Nussenzweig
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.W.C., M.E.W. and A.N. wrote the paper.

Corresponding authors

Correspondence to Keith W. Caldecott, Michael E. Ward or André Nussenzweig.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Genetics thanks Gerd Pfeifer, Ray Truant, and Anna Poetsch for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caldecott, K.W., Ward, M.E. & Nussenzweig, A. The threat of programmed DNA damage to neuronal genome integrity and plasticity. Nat Genet 54, 115–120 (2022). https://doi.org/10.1038/s41588-021-01001-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41588-021-01001-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing