Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis

Guerrero, Erika N.; Mitra, Joy; Wang, Haibo; Rangaswamy, Suganya; Hegde, Pavana M.; Basu, Priyadarshini; Rao, Krithika S.; Hegde, Muralidhar L.

doi:10.1093/hmg/ddz141

Cited by 12 publications

(15 citation statements)

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“…Importantly, neuronal cells lacking nuclear TDP-43 displayed increased genome instability and reduced survival compared with controls [79]. It was also reported that the ALS-linked TDP-43 Q331K mutation, previously described to weaken TDP-43 association with nucleic acids and to increase its propensity to form cytosolic aggregates [80], is associated with increased DNA damage accumulation, both in spinal cord tissues of sporadic patients and in cellular model systems [58]. In particular, such a mutation causes TDP-43 nuclear exclusion and hampers NHEJ, leading to defective DSB repair and persistent DNA damage [58].…”

Section: Altered Llps Is Involved In Neurodegenerationmentioning

confidence: 87%

“…It was also reported that the ALS-linked TDP-43 Q331K mutation, previously described to weaken TDP-43 association with nucleic acids and to increase its propensity to form cytosolic aggregates [80], is associated with increased DNA damage accumulation, both in spinal cord tissues of sporadic patients and in cellular model systems [58]. In particular, such a mutation causes TDP-43 nuclear exclusion and hampers NHEJ, leading to defective DSB repair and persistent DNA damage [58]. Recently, TDP-43 aggregates have been shown to possess the ability to be transferred from one neuronal cell to another, suggesting how aberrant LLPS occurring in a cell might also affect DSB repair in the surrounding cells [81].…”

Section: Altered Llps Is Involved In Neurodegenerationmentioning

confidence: 91%

“…Over the last two decades, mounting evidence has indicated the potential contribution of genome maintenance mechanisms to the onset and progression of neurological degenerative diseases [52][53][54][55]. Specifically, mutations predisposing to ALS were shown to alter DDR activation, impair repair, and increase DNA damage accumulation in motor neurons derived from patients induced pluripotent stem cells and in spinal cord tissues [56][57][58]. Although a causative role of DSB in the etiopathology of AD and PD remains to be conclusively demonstrated, multiple lines of evidence clearly indicate that increased levels of DSBs and/or their imperfect repair are associated with these disorders [53].…”

Section: Trends Trends In In Genetics Geneticsmentioning

confidence: 99%

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DNA Damage Triggers a New Phase in Neurodegeneration

et al. 2021

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Section: Altered Llps Is Involved In Neurodegenerationmentioning

confidence: 87%

Section: Altered Llps Is Involved In Neurodegenerationmentioning

confidence: 91%

Section: Trends Trends In In Genetics Geneticsmentioning

confidence: 99%

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DNA Damage Triggers a New Phase in Neurodegeneration

et al. 2021

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“…Interestingly, our follow-up study with ALS-associated mutant TDP-43 (Q331K) variant revealed that mutant TDP-43 mislocalized in the cytosol and trapped XRCC4, preventing its DNA damage-dependent nuclear translocation, eventually affecting Lig4 recruitment and activity. 6 Currently, genetic manipulation in C. elegans has emerged as a useful disease model to study ALS-associated neurodegeneration. In this study with a C. elegans model harboring truncated TDP-1, we documented higher mortality rates at larval stages, compared with wild-type nematodes, when challenged with irradiation.…”

Section: Mechanistic Role Of Tdp-43 In Nhej: Regulation Of Recruitment and Function Of Xrcc4-dna Lig4 Complexmentioning

confidence: 99%

A Commentary on TDP-43 and DNA Damage Response in Amyotrophic Lateral Sclerosis

Mitra

Hegde

2019

J Exp Neurosci

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Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. In a recent study, we reported for the first time that TDP-43 participates in the DNA damage response (DDR) in neurons, and its nuclear clearance in spinal motor neurons caused DNA double-strand break (DSB) repair defects in ALS. We documented that TDP-43 was a key component of the non-homologous end joining (NHEJ) pathway of DSB repair, which is likely the major pathway for repair of DSBs in post-mitotic neurons. We have also uncovered molecular insights into the role of TDP-43 in DSB repair and showed that TDP-43 acts as a scaffold in recruiting the XRCC4/DNA Ligase 4 complex at DSB damage sites and thus regulates a critical rate-limiting function in DSB repair. Significant DSB accumulation in the genomes of TDP-43-depleted, human neural stem cell-derived motor neurons as well as in ALS patient spinal cords with TDP-43 pathology, strongly supported a TDP-43 involvement in genome maintenance and toxicity-induced genome repair defects in ALS. In this commentary, we highlight our findings that have uncovered a link between TDP-43 pathology and impaired DNA repair and suggest potential possibilities for DNA repair-targeted therapies for TDP-43-ALS.

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“…Moreover, lines of evidence suggest that these CTFs can be produced via translation of an alternative transcript which is upregulated in ALS [20]. Recent studies proved that increased cytosolic 4 sequestration of the poly-ubiquitinated and aggregated forms of mutant TDP-43 correlates with higher levels of DNA strand breaks, activation of DDR factors such as phospho-ataxiatelangiectasia mutated (ATM), phospho-53BP1, γH2AX in SH-SY5Y lines expressing wildtype (WT) or Q331K-mutant TDP-43 [21]. TDP-43 depletion leads to increased sensitivity to various forms of DNA damage and mutation in the C-terminus glycine-rich lowcomplexity region (LC domain) associates with the loss of its nuclear function [22].…”

Section: Introductionmentioning

confidence: 99%

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Giannini¹,

Sproviero²,

Bayona-Feliú

et al. 2020

Preprint

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TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.

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Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis

Cited by 12 publications

References 0 publications

DNA Damage Triggers a New Phase in Neurodegeneration

DNA Damage Triggers a New Phase in Neurodegeneration

A Commentary on TDP-43 and DNA Damage Response in Amyotrophic Lateral Sclerosis

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

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