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Author Notes:

E-mail: Thomas.Kukar@emory.edu.

Author contributions: Q.D., C.J.H., and T.K. designed research; Q.D., C.J.H., G.T., K.F.H., W.W., M.G., M.E.M., D.W.D., and N.T.S. performed research; M.G., D.I., M.E.M., and D.W.D. contributed unpublished reagents/analytic tools; Q.D., C.J.H., W.W., M.G., N.T.S., and T.K. analyzed data; Q.D. and T.K. wrote the paper.

We thank Jonathan D. Glass and Deborah S. Cooper at the Emory ADRC/CND Brain and Tissue Bank for kindly providing samples; Marie Dutreix for graciously providing the siDNAs Dbait32H and Dbait8H; John Hedreen and Louis Fernandes of the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA (which is supported in part by National Institutes of Health Grant R24 MH06885) for tissue samples; and members of the Emory Center for Neurodegenerative Disease and the laboratories of Allan Levey and James Lah for helpful discussions.

The authors declare no competing financial interests.


Research Funding:

This work was supported by the National Institutes of Health (Grants P30NS069289, P50AG032362, and R00AG032362 to T.K. and Training Grant T32 “Training and translational research in Neurology” 2T32 NS 007480 to Q.D. and C.J.H.) and the Alzheimer's Association (New Investigator Research Grant to T.K.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • amyotrophic lateral sclerosis (ALS)
  • cytoplasmic translocation
  • DNA damage
  • frontotemporal lobar degeneration (FTLD)
  • Fused in Sarcoma (FUS)
  • phosphorylation

FUS is Phosphorylated by DNA-PK and Accumulates in the Cytoplasm after DNA Damage

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Journal Title:

Journal of Neuroscience Nursing


Volume 34, Number 23


, Pages 7802-7813

Type of Work:

Article | Final Publisher PDF


Abnormal cytoplasmic accumulation of Fused in Sarcoma (FUS) in neurons defines subtypes of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). FUS is a member of the FET protein family that includes Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 2N (TAF15). FET proteins are predominantly localized to the nucleus, where they bind RNA and DNA to modulate transcription, mRNA splicing, and DNA repair. In ALS cases with FUS inclusions (ALS-FUS), mutations in the FUS gene cause disease, whereas FTLD cases with FUS inclusions (FTLD-FUS) do not harbor FUS mutations. Notably, in FTLD-FUS, all FET proteins accumulate with their nuclear import receptor Transportin 1 (TRN1), in contrast ALS-FUS inclusions are exclusively positive for FUS. In the present study, we show that induction of DNA damage replicates several pathologic hallmarks of FTLD-FUS in immortalized human cells and primary human neurons and astrocytes. Treatment with the antibiotic calicheamicin γ1, which causes DNA double-strand breaks, leads to the cytoplasmic accumulation of FUS, TAF15, EWS, and TRN1. Moreover, cytoplasmic translocation of FUS is mediated by phosphorylation of its N terminus by the DNA-dependent protein kinase. Finally, we observed elevated levels of phospho-H2AX in FTLD-FUS brains, indicating that DNA damage occurs in patients. Together, our data reveal a novel regulatory mechanism for FUS localization in cells and suggest that DNA damage may contribute to the accumulation of FET proteins observed in human FTLD-FUS cases, but not in ALS-FUS. © 2014 the authors.

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© 2014 the authors

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