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.

C9orf72 functions in the nucleus to regulate DNA damage repair

Cell Death & Differentiation volume 30, pages 716–730 (2023)Cite this article

Subjects

Abstract

The hexanucleotide GGGGCC repeat expansion in the intronic region of C9orf72 is the most common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion-generated toxic RNAs and dipeptide repeats (DPRs) including poly-GR, have been extensively studied in neurodegeneration. Moreover, haploinsufficiency has been implicated as a disease mechanism but how C9orf72 deficiency contributes to neurodegeneration remains unclear. Here, we show that C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration by attenuating non-homologous end joining (NHEJ) repair. We demonstrate that C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency resulted in impaired NHEJ repair through attenuated DNA-PK complex assembly and DNA damage response (DDR) signaling. In mouse models, we found that C9orf72 deficiency exacerbated poly-GR-induced neuronal loss, glial activation, and neuromuscular deficits. Furthermore, DNA damage accumulated in C9orf72-deficient neurons that expressed poly-GR, resulting in excessive activation of PARP-1. PARP-1 inhibition rescued neuronal death in cultured neurons treated with poly-GR peptides. Together, our results support a pathological mechanism where C9orf72 haploinsufficiency synergizes with poly-GR-induced DNA double-strand breaks to exacerbate the accumulation of DNA damage and PARP-1 overactivation in C9orf72 ALS/FTD patients.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1: Accumulation of nuclear C9orf72 at DSB sites.
Fig. 2: C9orf72 deficiency leads to attenuated NHEJ repair.
Fig. 3: C9orf72 binds with DNA-PK complex to regulate DNA-PKcs phosphorylation.
Fig. 4: C9orf72 directly interacts with DNA-PKcs.
Fig. 5: C9orf72 promotes DNA-PK complex assembly and recruitment of Ligase 4/XCCR4 complex.
Fig. 6: C9orf72 deficiency exacerbates motor deficits and neurodegeneration in poly-GR expression mice.
Fig. 7: C9orf72 deficiency impairs NHEJ repair to induce DNA damage accumulation in poly-GR expression mice.
Fig. 8: C9orf72 deficiency exacerbates poly-GR-induced neuronal death by PARP-1 overactivation.

Data availability

The data generated to support the finding of this study are available from the corresponding author upon reasonable request.

References

  1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol. 2018;14:544–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 2013;80:415–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, et al. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017;20:1225–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee YB, Chen HJ, Peres JN, Gomez-Deza J, Attig J, Stalekar M, et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 2013;5:1178–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H, et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. 2013;125:413–23.

    Article  CAS  PubMed  Google Scholar 

  8. Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339:1335–8.

    Article  CAS  PubMed  Google Scholar 

  9. Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T, et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 2013;126:829–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77:639–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hao Z, Liu L, Tao Z, Wang R, Ren H, Sun H, et al. Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR. Nat Commun. 2019;10:2906.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Choi SY, Lopez-Gonzalez R, Krishnan G, Phillips HL, Li AN, Seeley WW, et al. C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo. Nat Neurosci. 2019;22:851–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 2016;167:774–88.e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang YJ, Gendron TF, Ebbert MTW, O’Raw AD, Yue M, Jansen-West K, et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat Med. 2018;24:1136–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol Cell. 2017;65:1044–55.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lopez-Gonzalez R, Lu Y, Gendron TF, Karydas A, Tran H, Yang D, et al. Poly(GR) in C9ORF72-related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron 2016;92:383–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Farg MA, Konopka A, Soo KY, Ito D, Atkin JD. The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis. Hum Mol Genet. 2017;26:2882–96.

    Article  CAS  PubMed  Google Scholar 

  18. Nihei Y, Mori K, Werner G, Arzberger T, Zhou Q, Khosravi B, et al. Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3. Acta Neuropathol. 2020;139:99–118.

    Article  PubMed  Google Scholar 

  19. Andrade NS, Ramic M, Esanov R, Liu W, Rybin MJ, Gaidosh G, et al. Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS/FTD. Mol Neurodegener. 2020;15:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang R, Xu X, Hao Z, Zhang S, Wu D, Sun H, et al. Poly-PR in C9ORF72-related amyotrophic lateral sclerosis/frontotemporal dementia causes neurotoxicity by clathrin-dependent endocytosis. Neurosci Bull. 2019;35:889–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maor-Nof M, Shipony Z, Lopez-Gonzalez R, Nakayama L, Zhang YJ, Couthouis J, et al. p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell 2021;184:689–708.e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lopez-Gonzalez R, Yang D, Pribadi M, Kim TS, Krishnan G, Choi SY, et al. Partial inhibition of the overactivated Ku80-dependent DNA repair pathway rescues neurodegeneration in C9ORF72-ALS/FTD. Proc Natl Acad Sci USA. 2019;116:9628–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Waite AJ, Baumer D, East S, Neal J, Morris HR, Ansorge O, et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging. 2014;35:1779.e5–e13.

    Article  CAS  PubMed  Google Scholar 

  24. Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, et al. Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol. 2015;78:568–83.

    Article  CAS  PubMed  Google Scholar 

  25. Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 2014;507:195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018;24:313–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhu Q, Jiang J, Gendron TF, McAlonis-Downes M, Jiang L, Taylor A, et al. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72. Nat Neurosci. 2020;23:615–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shao Q, Liang C, Chang Q, Zhang W, Yang M, Chen JF. C9orf72 deficiency promotes motor deficits of a C9ALS/FTD mouse model in a dose-dependent manner. Acta Neuropathol Commun. 2019;7:32.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Su MY, Fromm SA, Zoncu R, Hurley JH. Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD. Nature. 2020;585:251–5.

  30. Ugolino J, Ji YJ, Conchina K, Chu J, Nirujogi RS, Pandey A, et al. Loss of C9orf72 enhances autophagic activity via deregulated mTOR and TFEB signaling. PLoS Genet. 2016;12:e1006443.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L, et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 2016;35:1656–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang M, Liang C, Swaminathan K, Herrlinger S, Lai F, Shiekhattar R, et al. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. 2016;2:e1601167.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang Y, Burberry A, Wang JY, Sandoe J, Ghosh S, Udeshi ND, et al. The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Genes Dev. 2018;32:929–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee HC, et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep. 2016;6:23204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, Stewart MH, et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med. 2016;8:347ra93.

    Article  PubMed  PubMed Central  Google Scholar 

  36. O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 2016;351:1324–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. McCauley ME, O’Rourke JG, Yanez A, Markman JL, Ho R, Wang X, et al. C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature. 2020;585:96–101.

  38. Wang T, Liu H, Itoh K, Oh S, Zhao L, Murata D, et al. C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly. Cell Metab. 2021;33:531–46.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sullivan PM, Zhou X, Robins AM, Paushter DH, Kim D, Smolka MB, et al. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun. 2016;4:51.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Laflamme C, McKeever PM, Kumar R, Schwartz J, Kolahdouzan M, Chen CX, et al. Implementation of an antibody characterization procedure and application to the major ALS/FTD disease gene C9ORF72. Elife. 2019;8.

  41. Amick J, Roczniak-Ferguson A, Ferguson SM. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol Biol Cell. 2016;27:3040–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, et al. Activity-Induced DNA breaks govern the expression of neuronal early-response genes. Cell 2015;161:1592–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Janicki SM, Tsukamoto T, Salghetti SE, Tansey WP, Sachidanandam R, Prasanth KV, et al. From silencing to gene expression: real-time analysis in single cells. Cell 2004;116:683–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Moore S, Berger ND, Luijsterburg MS, Piett CG, Stanley FKT, Schrader CU, et al. The CHD6 chromatin remodeler is an oxidative DNA damage response factor. Nat Commun. 2019;10:241.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Han J, Yu M, Bai Y, Yu J, Jin F, Li C, et al. Elevated CXorf67 Expression in PFA Ependymomas suppresses DNA repair and sensitizes to PARP inhibitors. Cancer Cell. 2020;38:844–56.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Madabhushi R, Pan L, Tsai LH. DNA damage and its links to neurodegeneration. Neuron 2014;83:266–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell. 2005;120:497–512.

    Article  CAS  PubMed  Google Scholar 

  48. Dobbin MM, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, et al. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci. 2013;16:1008–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC, et al. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013;16:1383–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V. DNA end joining becomes less efficient and more error-prone during cellular senescence. Proc Natl Acad Sci USA. 2004;101:7624–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Weterings E, Chen DJ. The endless tale of non-homologous end-joining. Cell Res. 2008;18:114–24.

    Article  CAS  PubMed  Google Scholar 

  52. Kurimasa A, Kumano S, Boubnov NV, Story MD, Tung CS, Peterson SR, et al. Requirement for the kinase activity of human DNA-dependent protein kinase catalytic subunit in DNA strand break rejoining. Mol Cell Biol. 1999;19:3877–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lempiainen H, Halazonetis TD. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J. 2009;28:3067–73.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332:237–48.

    Article  CAS  PubMed  Google Scholar 

  55. Chen BP, Chan DW, Kobayashi J, Burma S, Asaithamby A, Morotomi-Yano K, et al. Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double-strand breaks. J Biol Chem. 2005;280:14709–15.

    Article  CAS  PubMed  Google Scholar 

  56. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, et al. GammaH2AX and cancer. Nat Rev Cancer. 2008;8:957–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185:232–40.

    Article  PubMed  Google Scholar 

  58. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006;7:710–23.

    Article  CAS  PubMed  Google Scholar 

  59. Andrabi SA, Umanah GK, Chang C, Stevens DA, Karuppagounder SS, Gagne JP, et al. Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci USA. 2014;111:10209–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fouquerel E, Goellner EM, Yu Z, Gagne JP, Barbi de Moura M, Feinstein T, et al. ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion. Cell Rep. 2014;8:1819–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang Y, An R, Umanah GK, Park H, Nambiar K, Eacker SM, et al. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science. 2016;354.

  62. Dawson TM, Dawson VL. Mitochondrial mechanisms of neuronal cell death: potential therapeutics. Annu Rev Pharm Toxicol. 2017;57:437–54.

    Article  CAS  Google Scholar 

  63. Park H, Kam TI, Dawson TM, Dawson VL. Poly (ADP-ribose) (PAR)-dependent cell death in neurodegenerative diseases. Int Rev Cell Mol Biol. 2020;353:1–29.

    Article  CAS  PubMed  Google Scholar 

  64. McGurk L, Mojsilovic-Petrovic J, Van Deerlin VM, Shorter J, Kalb RG, Lee VM, et al. Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2018;6:84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Murata MM, Kong X, Moncada E, Chen Y, Imamura H, Wang P, et al. NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival. Mol Biol Cell. 2019;30:2584–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fan J, Dawson TM, Dawson VL. Cell death mechanisms of neurodegeneration. Adv Neurobiol. 2017;15:403–25.

    Article  PubMed  Google Scholar 

  67. Kanai M, Hanashiro K, Kim SH, Hanai S, Boulares AH, Miwa M, et al. Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nat Cell Biol. 2007;9:1175–83.

    Article  CAS  PubMed  Google Scholar 

  68. Fischbach A, Kruger A, Hampp S, Assmann G, Rank L, Hufnagel M, et al. The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1. Nucleic Acids Res. 2018;46:804–22.

    Article  CAS  PubMed  Google Scholar 

  69. Dong Z, Chen W, Chen C, Wang H, Cui W, Tan Z, et al. CUL3 deficiency causes social deficits and anxiety-like behaviors by impairing excitation-inhibition balance through the promotion of cap-dependent translation. Neuron 2020;105:475–90.e6.

    Article  CAS  PubMed  Google Scholar 

  70. Li L, Cao Y, Wu H, Ye X, Zhu Z, Xing G, et al. Enzymatic activity of the scaffold Protein Rapsyn for Synapse formation. Neuron 2016;92:1007–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tung YT, Peng KC, Chen YC, Yen YP, Chang M, Thams S, et al. Mir-17 approximately 92 confers motor neuron subtype differential resistance to ALS-associated degeneration. Cell Stem Cell. 2019;25:193–209.e7.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 serves as a coreceptor of agrin. Neuron 2008;60:285–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mitra J, Guerrero EN, Hegde PM, Liachko NF, Wang H, Vasquez V, et al. Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci USA. 2019;116:4696–705.

  74. Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, et al. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron. 2004;41:549–61.

    Article  CAS  PubMed  Google Scholar 

  75. Gyori BM, Venkatachalam G, Thiagarajan PS, Hsu D, Clement MV. OpenComet: an automated tool for comet assay image analysis. Redox Biol. 2014;2:457–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bennardo N, Cheng A, Huang N, Stark JM. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet. 2008;4:e1000110.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Shen C, Lu Y, Zhang B, Figueiredo D, Bean J, Jung J, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest. 2013;123:5190–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank XL, CF, and ZY from the Molecular Imaging Core Facility (MICF); PH, and CZ from the Multi-Omics Core Facility (MOCF); and YX, XR, and JL from the Molecular and Cell Biology Core Facility (MCBCF) at the School of Life Science and Technology, ShanghaiTech University for providing technical support. We also thank W. Wang (Interdisciplinary Research Center on Biology and Chemistry, China) for providing C9ALS iPSCs, V. Gorbunova (University of Rochester, USA) for providing NHEJ reporter constructs, and D. Spector (Cold Spring Harbor Laboratory, USA) for providing U2OS-LacO cells. This study was supported by grants from the National Natural Science Foundation of China (91949117, 31871044 to LL).

Author information

Author notes

  1. These authors contributed equally: Liying He, Jiaqi Liang.

Authors and Affiliations

  1. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Liying He, Jiaqi Liang, Chaonan Chen, Yihui Shen, Shuangshuang Sun & Lei Li

  2. University of Chinese Academy of Sciences, Beijing, China

    Liying He, Jiaqi Liang, Yihui Shen & Shuangshuang Sun

  3. Institute of Brain-Intelligence Technology, Zhangjiang Laboratory, Shanghai, China

    Jijun Chen

Authors
  1. Liying He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiaqi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chaonan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jijun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yihui Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuangshuang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LL and LYH designed the experiments and wrote the manuscript. LYH and JQL performed and analyzed most of the experiments; JJC generated C9orf72−/− NPCs and performed neuron differentiation. CNC, SSS, and YHS contributed to data analyses.

Corresponding author

Correspondence to Lei Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Our study did not require ethical approval.

Additional information

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

Edited by M Piacentini

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

He, L., Liang, J., Chen, C. et al. C9orf72 functions in the nucleus to regulate DNA damage repair. Cell Death Differ 30, 716–730 (2023). https://doi.org/10.1038/s41418-022-01074-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41418-022-01074-0

Search

Advanced search

Quick links