Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2019-03, Vol.116 (10), p.4696-4705

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.