Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane

Fontana, Gabriele; Heß, Daniel; Reinert, Julia K.; Mattarocci, Stefano; Falquet, Benoît; Klein, Dominique; Shore, David; Thomä, Nicolas H.; Rass, Ulrich

doi:10.1038/s41467-019-10349-z

Cited by 37 publications

(35 citation statements)

References 70 publications

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“…It is therefore plausible that TOP1ccs This is a particularly appealing model considering that TEX264 and SPRTN co-localise with nascent DNA at the nuclear envelope, where heterochromatin is tethered. Alternatively, TOP1ccs may be relocalised to the nuclear envelope, as has been demonstrated for other SUMOylated proteins and some types of DNA lesions [73][74][75] . It is perhaps less likely that TEX264 only operates on a specific subset of TOP1ccs, since numerous experimental approaches demonstrated that TEX264 and TDP1 act in the same pathway to repair endogenous TOP1ccs.…”

Section: Discussionmentioning

confidence: 81%

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: Discussionmentioning

confidence: 81%

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

et al. 2020

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“…It is also required for immunoglobulin class-switch recombination during the germinal centre reaction for humoral antibody immunity (Di Virgilio et al, 2013). RIF1 is involved in telomere homeostasis and was recently found to be post-translationally S-acylated, identifying a novel posttranslational modification regulating DNA repair (Fontana et al, 2019). Post-translational deimination has hitherto not been described.…”

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confidence: 99%

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Criscitiello

Kraev

Lange

2020

Molecular Immunology

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A B S T R A C TPeptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which posttranslationally convert arginine into citrulline in target proteins in an irreversible manner, causing functional and structural changes in target proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for protein moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock proteins. In serum, 60 deiminated proteins were identified that were not in EVs, and 25 deiminated proteins were found to be unique to EVs, with 43 shared deiminated protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70 kDa size. This is the first report of deiminated proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.

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“…It is noteworthy that a new study has been published linking RIF1 S-acylation by the DHHC family palmitoyl acyltransferase Pfa4 to DSB repair in yeast (Fontana et al, 2019). As no RIF1 orthologue exists in plants the PAT21 mediated process must be mechanistically different.…”

Section: Discussionmentioning

confidence: 99%

Both male and female gametogenesis require a fully functional protein S‐acyl transferase 21 in Arabidopsis thaliana

Morgan

et al. 2019

The Plant Journal

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Summary S‐Acylation is a reversible post‐translational lipid modification in which a long chain fatty acid covalently attaches to specific cysteine(s) of proteins via a thioester bond. It enhances the hydrophobicity of proteins, contributes to their membrane association and plays roles in protein trafficking, stability and signalling. A family of Protein S‐Acyl Transferases (PATs) is responsible for this reaction. PATs are multi‐pass transmembrane proteins that possess a catalytic Asp−His−His−Cys cysteine‐rich domain (DHHC‐CRD). In Arabidopsis, there are currently 24 such PATs, five having been characterized, revealing their important roles in growth, development, senescence and stress responses. Here, we report the functional characterization of another PAT, AtPAT21, demonstrating the roles it plays in Arabidopsis sexual reproduction. Loss‐of‐function mutation by T‐DNA insertion in AtPAT21 results in the complete failure of seed production. Detailed studies revealed that the sterility of the mutant is caused by defects in both male and female sporogenesis and gametogenesis. To determine if the sterility observed in atpat21‐1 was caused by upstream defects in meiosis, we assessed meiotic progression in pollen mother cells and found massive chromosome fragmentation and the absence of synapsis in the initial stages of meiosis. Interestingly, the fragmentation phenotype was substantially reduced in atpat21‐1 spo11‐1 double mutants, indicating that AtPAT21 is required for repair, but not for the formation, of SPO11‐induced meiotic DNA double‐stranded breaks (DSBs) in Arabidopsis. Our data highlight the importance of protein S‐acylation in the early meiotic stages that lead to the development of male and female sporophytic reproductive structures and associated gametophytes in Arabidopsis.

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Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane

Cited by 37 publications

References 70 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

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Both male and female gametogenesis require a fully functional protein S‐acyl transferase 21 in Arabidopsis thaliana

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