The p97–Ataxin 3 complex regulates homeostasis of the
            <scp>DNA</scp>
            damage response E3 ubiquitin ligase
            <scp>RNF</scp>
            8

Singh, Abhay Narayan; Oehler, Judith; Torrecilla, Ignacio; Kilgas, Susan; Li, Shudong; Vaz, Bruno; Guérillon, Claire; Fielden, John; Hernández-Carralero, Esperanza; Cabrera, Elisa; Tullis, Iain D. C.; Meerang, Mayura; Barber, Paul R.; Freire, Raimundo; Parsons, Jason L.; Vojnovic, Borivoj; Kiltie, Anne E.; Mailand, Niels; Ramadan, Kristijan

doi:10.15252/embj.2019102361

Cited by 44 publications

(40 citation statements)

References 88 publications

(133 reference statements)

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“…1A). By using energy generated from ATP hydrolysis, p97 remodels its substrates and extracts them from macromolecular structures such as chromatin [27][28][29][30][31][32][33] . Given this known role of p97, and since Cdc48 has been implicated in TOP1cc repair, we investigated whether p97 contributes to TOP1cc processing in human cells.…”

Section: Resultsmentioning

confidence: 99%

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

et al. 2020

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Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate-a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)-is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3' phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.

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Section: Resultsmentioning

confidence: 99%

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

et al. 2020

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“…The involvement of DSB repair in ALS/FTD is further substantiated by the observation that other proteins mutated in fALS such as valosin-containing protein (VCP)/p97 and sequestosome 1(SQSTM1)/p62 are linked to NHEJ [ 69 , 70 ]. VCP has been shown to directly interact with the canonical NHEJ proteins Ku70/80 [ 69 ] as well as with ring finger proteins (RNF) 8/168 [ 71 ] to balance DNA repair pathway choice and promote cell survival. This process is done in close correlation with SQSTM1/p62 that via interactions with ATM, RAD50 and RNF168 also regulates the choice between HR and NHEJ in favour of the latter [ 70 ].…”

Section: Tdp43 Mislocalization Impairs Ddrmentioning

confidence: 99%

The role of DNA damage response in amyotrophic lateral sclerosis

Sun

Curle

Haider

et al. 2020

Essays in Biochemistry

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Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.

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“…As CuET impairs the p97/NPL4 pathway that is directly implicated in several processes linked to DNA repair and replication [35], it remains to be seen whether the replication interference could be explained by impacting such processes, including DNA replication, translesion synthesis, DNA-protein crosslinks repair, or termination of replication [36], possibly in a combination. Moreover, p97, together with diverse cofactors, is also directly involved in DSB repair, contributing to the recruitment of the 53BP1 repair factor [37] and also other DDR proteins [38][39][40]. On the other hand, also indirect effects of NPL4 aggregation, for example, the triggered heat-shock response, could plausibly contribute to the phenotypes observed here.…”

Section: Discussionmentioning

confidence: 80%

Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway

Majera

Škrott

Chroma

et al. 2020

Cells

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Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.

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The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

Cited by 44 publications

References 88 publications

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

The role of DNA damage response in amyotrophic lateral sclerosis

Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway

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