Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects

Joy Mitra, Erika N. Guerrero, Pavana M. Hegde, Nicole F. Liachko, Haibo Wang, Velmarini Vasquez, Junling Gao, Arvind Pandey, J. Paul Taylor, Brian C. Kraemer, Ping Wu, Istvan Boldogh, Ralph M. Garruto, Sankar Mitra, K. S. Rao, Muralidhar L. Hegde

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.

Original languageEnglish (US)
Pages (from-to)4696-4705
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number10
DOIs
StatePublished - Jan 1 2019

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Keywords

  • Amyotrophic lateral sclerosis
  • DNA damage response
  • DNA double-strand break repair
  • Neurodegeneration
  • TDP-43

ASJC Scopus subject areas

  • General

Cite this

Mitra, J., Guerrero, E. N., Hegde, P. M., Liachko, N. F., Wang, H., Vasquez, V., Gao, J., Pandey, A., Paul Taylor, J., Kraemer, B. C., Wu, P., Boldogh, I., Garruto, R. M., Mitra, S., Rao, K. S., & Hegde, M. L. (2019). Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proceedings of the National Academy of Sciences of the United States of America, 116(10), 4696-4705. https://doi.org/10.1073/pnas.1818415116