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dc.contributor.authorMitra, Joy
dc.contributor.authorGuerrero, Erika N
dc.contributor.authorHegde, Pavana M
dc.contributor.authorLiachko, Nicole F
dc.contributor.authorWang, Haibo
dc.contributor.authorVasquez, Velmarini
dc.contributor.authorGao, Junling
dc.contributor.authorPandey, Arvind
dc.contributor.authorTaylor, J Paul
dc.contributor.authorKraemer, Brian C
dc.contributor.authorWu, Ping
dc.contributor.authorBoldogh, Istvan
dc.contributor.authorGarruto, Ralph M
dc.contributor.authorMitra, Sankar
dc.contributor.authorRao, KS Jagannatha
dc.contributor.authorHegde, Muralidhar L
dc.date.accessioned2020-06-16T00:57:27Z
dc.date.available2020-06-16T00:57:27Z
dc.date.issued2019-03-05
dc.identifier.otherhttps://doi.org/10.1073/pnas.1818415116
dc.identifier.urihttp://repositorio-indicasat.org.pa/handle/123456789/69
dc.descriptionGenome 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.en_US
dc.description.abstractGenome 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.en_US
dc.language.isoenen_US
dc.subjectTDP-43en_US
dc.subjectDNA damage responseen_US
dc.subjectDNA double-strand break repairen_US
dc.subjectamyotrophic lateralen_US
dc.subjectsclerosisen_US
dc.subjectneurodegenerationen_US
dc.titleMotor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defectsen_US
dc.typeArticleen_US


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