Affinage

SPRTN

DNA-dependent metalloprotease SPRTN · UniProt Q9H040

Length
489 aa
Mass
55.1 kDa
Annotated
2026-04-28
65 papers in source corpus 35 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPRTN is a DNA-dependent metalloprotease essential for the repair of DNA-protein crosslinks (DPCs), functioning both during and independently of DNA replication to maintain genome stability (PMID:27871366, PMID:36681662). Its SprT domain harbors a Zn²⁺-dependent active site allosterically activated by ssDNA/dsDNA junction binding via a bipartite DNA-recognition mechanism and by polyubiquitin chains on DPC substrates sensed through a dedicated ubiquitin-binding interface on the protease domain; SPRTN is recruited to chromatin through its PIP box (PCNA), UBZ domain (ubiquitin), and SHP box (p97/VCP), and cooperates with p97-Ufd1-Npl4 to unfold tightly folded crosslinked proteins for degradation (PMID:30893605, PMID:32853547, PMID:40691134, PMID:35469923). SPRTN activity is tightly controlled by a monoubiquitylation-triggered autocatalytic inactivation loop counteracted by deubiquitylases USP7 and USP11, and by VCPIP1-mediated deubiquitylation followed by acetylation that promotes chromatin relocalization; beyond DPC proteolysis, SPRTN cleaves CHK1 to activate the ATR-CHK1 replication checkpoint and cleaves MRE11 to modulate homologous recombination (PMID:33348378, PMID:32649882, PMID:31316063, PMID:33558481). Biallelic germline loss-of-function mutations in SPRTN cause Ruijs-Aalfs syndrome, a progeroid disorder with genomic instability and early-onset hepatocellular carcinoma (PMID:25261934).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 High

    Before SPRTN's enzymatic activity was known, its recruitment mechanism to stalled replication forks was established: SPRTN uses a PIP box and UBZ domain to bind ubiquitylated PCNA and an SHP box to recruit p97/VCP, placing it as a scaffold coordinating translesion synthesis polymerase access and exchange at damage sites.

    Evidence Co-IP, domain mutant analysis, UV damage foci, and siRNA knockdown in human cells and C. elegans

    PMID:22681887 PMID:22902628 PMID:22987070 PMID:23042605 PMID:23042607 PMID:23254330

    Open questions at the time
    • The catalytic function of the SprT metalloprotease domain was unknown at this stage
    • Whether SPRTN had enzymatic activity or served purely as an adaptor was unresolved
    • The relationship between SPRTN's TLS regulation role and its later-discovered DPC protease role was unclear
  2. 2014 High

    Genetic studies established that SPRTN is essential for genome stability in vivo: biallelic SPRTN mutations were identified as the cause of Ruijs-Aalfs syndrome (premature aging and hepatocellular carcinoma), and the Drosophila ortholog maternal haploid demonstrated a conserved role in replication fork protection and paternal genome integrity.

    Evidence Patient-derived cell lines with SPRTN mutations, replication stress and checkpoint assays, Drosophila maternal effect genetics and live imaging

    PMID:25242033 PMID:25261934

    Open questions at the time
    • The molecular substrate(s) of SPRTN protease activity in vivo were not yet identified
    • Whether the progeroid phenotype results from DPC accumulation specifically was not demonstrated
  3. 2016 High

    The central mechanistic breakthrough established SPRTN as a bona fide DNA-dependent metalloprotease that cleaves DPC substrates during S-phase, with protease activity requiring DNA binding and regulated by a conformational DNA switch and a ubiquitin switch controlling chromatin access; structural determination of the PCNA–PIP box interaction provided the atomic basis for PCNA recruitment.

    Evidence In vitro protease assays with purified SPRTN, DPC repair assays in patient cells, crystal structures of SprT domain and PCNA–PIP box complex, active-site mutagenesis

    PMID:27084448 PMID:27852435 PMID:27871365 PMID:27871366

    Open questions at the time
    • The precise DNA structural features required for protease activation were not yet defined
    • Whether SPRTN operated independently of the proteasome during replication-coupled DPC repair was unknown
  4. 2018 High

    Using Xenopus egg extracts, SPRTN and the proteasome were shown to act as independent, parallel DPC proteases during replication; SPRTN activation did not require DPC polyubiquitylation but depended on nascent strand extension to near the lesion, establishing polymerase stalling as the replication-coupled trigger.

    Evidence Reconstituted replication-coupled DPC repair in Xenopus egg extracts with immunodepletion of SPRTN or proteasome

    PMID:30595436

    Open questions at the time
    • Whether polyubiquitylation contributes to SPRTN activation in mammalian systems was unresolved (later shown to be important)
    • The mechanism by which polymerase stalling is sensed and transduced to SPRTN activation was unclear
  5. 2019 High

    The crystal structure of the SprT domain revealed a Zn²⁺-binding sub-domain (ZBD) that shields the active site and contains an ssDNA-binding pocket; simultaneously, SPRTN was shown to proteolytically cleave CHK1 to activate the ATR-CHK1 checkpoint, with CHK1 reciprocally phosphorylating SPRTN to enhance its chromatin recruitment, establishing a cross-activation loop.

    Evidence X-ray crystallography with functional mutagenesis; in vitro protease assay with purified SPRTN and CHK1, phosphorylation assays, chromatin fractionation

    PMID:30893605 PMID:31316063

    Open questions at the time
    • The full allosteric mechanism linking DNA binding to active-site opening was not resolved
    • Whether CHK1 cleavage occurs at all DPC-containing forks or is context-specific was not established
  6. 2020 High

    Three regulatory layers were clarified: SPRTN recognizes DPCs specifically at ssDNA/dsDNA junctions via a bipartite DNA-binding strategy (NMR); TEX264 forms a complex with p97 and SPRTN to recognize TOP1 cleavage complexes; and VCPIP1 deubiquitylates SPRTN downstream of ATM/ATR signaling, with subsequent acetylation promoting chromatin relocalization.

    Evidence NMR spectroscopy with defined DPC substrates; reciprocal Co-IP and iPOND for TEX264-p97-SPRTN; in vitro deubiquitylation assays, mouse knockout model for VCPIP1

    PMID:32152270 PMID:32649882 PMID:32853547

    Open questions at the time
    • How TEX264 hands off unfolded TOP1 to SPRTN's active site was not structurally resolved
    • The acetylation sites on SPRTN and their structural effects were not mapped
  7. 2021 High

    The ubiquitin-dependent autoregulation of SPRTN was dissected: monoubiquitylation triggers autocatalytic self-cleavage in trans and proteasomal degradation, counteracted by USP7 and USP11; SPRTN was also shown to cleave MRE11 to attenuate HR repair, and to degrade trapped PARP1-DNA complexes during S-phase; additionally, DPC SUMOylation was found to channel repair toward SPRTN proteolysis rather than HR.

    Evidence In vitro ubiquitylation/deubiquitylation and cleavage assays, mass spectrometry mapping of MRE11 cleavage site, PARP trapper sensitivity assays, DPC repair epistasis with SUMO pathway

    PMID:33348378 PMID:33558481 PMID:33567341 PMID:34551432 PMID:34879279

    Open questions at the time
    • The E3 ubiquitin ligase(s) responsible for SPRTN monoubiquitylation remain unidentified
    • Whether MRE11 cleavage by SPRTN is a physiological regulatory event or a pathological consequence of aberrant protease activity is not settled
    • The relative contributions of SPRTN vs. proteasome to trapped PARP1 clearance in patient cells need quantitation
  8. 2022 High

    Full reconstitution with purified components demonstrated that p97/VCP (with Ufd1-Npl4 adaptor) unfolds polyubiquitinated DPCs to enable SPRTN proteolysis of tightly folded substrates that SPRTN alone cannot cleave, establishing the mechanistic basis for p97-SPRTN cooperation.

    Evidence In vitro reconstitution with purified p97, Ufd1-Npl4, SPRTN, and fluorescent DPC reporter substrates

    PMID:35469923

    Open questions at the time
    • Whether all in vivo DPC substrates require p97-mediated unfolding or only a subset was not determined
    • The ubiquitin chain type and length threshold required for p97 engagement were not defined
  9. 2023 High

    SPRTN was shown to operate in replication-independent global-genome DPC repair requiring SUMO-targeted ubiquitylation of the protein adduct, expanding SPRTN's role beyond S-phase; SPRTN proteolysis was established as an upstream step generating peptide remnants required for subsequent γH2AX signaling and DNA repair factor recruitment, and epistasis with TDP1 was mapped for different DPC substrates.

    Evidence PxP DPC purification technique, engineered patient-variant cell lines, STAR assay for DPC kinetics, zebrafish and human RPE1 genetic epistasis

    PMID:36681662 PMID:36718861 PMID:37788708

    Open questions at the time
    • The nuclease(s) that remove SPRTN-generated peptide remnants from DNA in the global-genome pathway are incompletely characterized
    • How SPRTN is recruited to DPCs outside of S-phase without PCNA engagement is not fully resolved
  10. 2025 High

    A second ubiquitin-sensing mechanism was discovered: polyubiquitin chains on DPC substrates allosterically activate SPRTN by binding a previously unrecognized ubiquitin interface (USD) on the SprT protease domain, distinct from the canonical UBZ domain, promoting an open active conformation and yielding ~67-fold enhanced protease activation toward polyubiquitinated DPCs.

    Evidence In vitro DPC repair reconstitution, NMR spectroscopy, MD simulations, site-directed mutagenesis, quantitative protease activation assays with polyubiquitinated substrates

    PMID:40685547 PMID:40691134

    Open questions at the time
    • A full atomic-resolution structure of SPRTN in the activated conformation bound to a polyubiquitinated DPC substrate is lacking
    • How the UBZ and USD ubiquitin-sensing modules cooperate or divide labor in vivo is not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the identity of the E3 ligase(s) mediating SPRTN monoubiquitylation, the full structural basis for the allosteric transition from closed to open protease conformation, whether SPRTN's non-DPC substrates (CHK1, MRE11) represent regulated signaling or collateral cleavage, and the mechanistic basis for tissue-specific cancer predisposition (hepatocellular carcinoma) in Ruijs-Aalfs syndrome.
  • No E3 ligase identified for SPRTN monoubiquitylation
  • No full-length SPRTN structure in active or inactive state
  • Tissue-specific oncogenic mechanism in Ruijs-Aalfs syndrome is unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0003677 DNA binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005694 chromosome 4 GO:0005654 nucleoplasm 2
Pathway
R-HSA-73894 DNA Repair 7 R-HSA-69306 DNA Replication 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-1643685 Disease 1
Partners
CHEK1PCNAPOLD3TEX264USP11USP7VCPVCPIP1
Complex memberships
SPRTN-p97/VCP-Ufd1-Npl4TEX264-p97-SPRTN

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 SPRTN is a DNA-dependent metalloprotease that cleaves various DNA-binding proteins (DPC substrates) during S-phase; its protease activity requires DNA binding, is coupled to DNA replication fork progression, and is essential for DPC repair. Patient cells with SPRTN mutations are hypersensitive to DPC-inducing agents due to defective replication fork progression. In vitro protease assay with purified SPRTN, cell-based DPC repair assays, patient-derived cell lines, DNA replication fork progression assays Molecular cell High 27852435 27871365 27871366
2016 SPRTN protease activity is controlled by a DNA switch: single-stranded DNA induces conformational activation. A ubiquitin switch controls SPRTN chromatin accessibility. SPRTN also undergoes regulatory autocatalytic cleavage (self-cleavage in trans). Biochemical assays, structural studies, active-site mutagenesis, ubiquitin-binding domain mutants, cellular chromatin fractionation Molecular cell High 27871365
2019 Crystal structure of the human SPRTN SprT domain bound to single-stranded DNA reveals a Zn2+-binding sub-domain (ZBD) that shields the metalloprotease active site; ZBD contains an ssDNA-binding pocket formed by aromatic residues, and mutations of these residues diminish SPRTN protease activity. X-ray crystallography, site-directed mutagenesis, in vitro protease activity assay Cell reports High 30893605
2020 SPRTN displays strict DNA structure-specific protease activity: it cleaves DPCs at or near disruptions in double-stranded DNA (i.e., ssDNA/dsDNA junctions), but does not cleave proteins crosslinked to intact dsDNA or ssDNA. NMR spectroscopy revealed a bipartite DNA-binding strategy with two distinct interfaces recognizing different structural features. In vitro protease assay with defined DPC model substrates, NMR spectroscopy Molecular cell High 32853547
2018 In Xenopus egg extracts, SPRTN and the proteasome act as independent DPC proteases during replication-coupled DPC repair. SPRTN-mediated DPC degradation does not require DPC polyubiquitylation but depends on nascent strand extension to within a few nucleotides of the lesion, implying polymerase stalling activates SPRTN on both leading and lagging strand templates. Xenopus egg extract replication assay, immunodepletion of SPRTN or proteasome components, DPC repair biochemical assay Molecular cell High 30595436
2012 DVC1/SPRTN (C1orf124) accumulates at stalled replication forks via its UBZ ubiquitin-binding domain and PIP box PCNA-interacting motif, and recruits the p97 AAA-ATPase/segregase to sites of replication stress via a conserved SHP box, facilitating p97-dependent removal of TLS polymerase η from monoubiquitylated PCNA. Co-immunoprecipitation, laser/UV damage localization, UBZ/PIP/SHP domain mutants, siRNA knockdown in human cells, C. elegans genetics Nature structural & molecular biology High 23042605 23042607
2012 Spartan/C1orf124 specifically recognizes ubiquitylated PCNA via its PIP box and UBZ domain, colocalizes and interacts with Rad18, and promotes a feed-forward loop that enhances PCNA ubiquitylation and TLS polymerase η localization to UV damage sites. In vitro ubiquitylated PCNA binding assay, Co-IP, UV damage foci, siRNA knockdown, PIP/UBZ domain mutants Molecular cell High 22681887
2012 Spartan binds ubiquitin-modified PCNA and protects it from deubiquitylation by USP1, thereby maintaining elevated levels of Ub-PCNA and facilitating TLS polymerase access to stalled replication forks. Co-IP with ubiquitylated PCNA, in vitro deubiquitylation protection assay, siRNA knockdown, UV sensitivity assays, sister chromatid exchange assays Nucleic acids research Medium 22987070
2012 The SprT metalloprotease domain of Spartan directly interacts with POLD3 (accessory subunit of replicative Pol δ) and suppresses POLD3-dependent error-prone TLS through Rev1/Pol ζ; Spartan depletion induces complex formation of POLD3 with Rev1 and Pol ζ and elevates mutagenesis. Co-IP, pulldown, mutagenesis of SprT domain, UV mutagenesis assays, siRNA knockdown Nucleic acids research Medium 23254330
2012 C1orf124/Spartan binds POLD3 and PDIP1 under normal conditions but preferentially associates with TLS polymerase η (POLH) upon UV damage; it also binds VCP/p97 via an SHP domain, and cellular UV resistance requires both the VCP interaction and PCNA binding. Co-IP, UV damage foci, siRNA knockdown, domain mutant analysis The Journal of biological chemistry Medium 22902628
2016 Crystal structure of human PCNA in complex with the DVC1/SPRTN PIP box peptide reveals the molecular basis for the YF-type PIP box–PCNA interaction; substitution of Y331 with Phe severely reduces PCNA binding affinity. X-ray crystallography, binding affinity assays with mutant peptides Biochemical and biophysical research communications High 27084448
2016 SPRTN DNA-binding activity is required for targeting TLS polymerase η to UV damage sites in cells; a DNA-binding mutant of SPRTN fails to recruit Pol η appropriately, demonstrating that SPRTN's DNA binding directly regulates damage tolerance. In vitro DNA binding assay with purified SPRTN, DNA-binding mutant, live-cell UV damage foci of Pol η, epistasis DNA repair Medium 27838458
2017 Purified human Spartan has DNA-dependent protease activity that degrades proteins bound to DNA; Spartan is required for direct DPC removal in vivo, facilitates repair of formaldehyde-induced DPCs in later replication phases, and epistasis analysis places this function in the RAD6-RAD18 DNA damage tolerance pathway. In vitro protease assay with purified protein, BrdU comet assay, DNA fibre assay, genetic epistasis with RAD6-RAD18 pathway Nucleic acids research High 28053116
2017 Spartan deficiency causes accumulation of Topoisomerase 1 covalently linked to DNA (TOP1-DPCs) in mouse livers, demonstrating that SPRTN is required for removal of endogenous TOP1 DPCs in vivo. Sprtn hypomorphic mouse model, ICE (in vivo complex of enzyme) assay for TOP1-DPCs, DNA damage markers, aneuploidy analysis Nucleic acids research High 28199696
2019 SPRTN activates the ATR-CHK1 signalling cascade during physiological DNA replication by proteolytically cleaving the C-terminal/inhibitory part of CHK1 to liberate N-terminal kinase-active fragments; reciprocally, CHK1 phosphorylates SPRTN at its C-terminal regulatory domain to stimulate SPRTN chromatin recruitment, forming a cross-activation loop. In vitro protease assay with purified SPRTN and CHK1, phosphorylation assays, chromatin fractionation, siRNA knockdown, mass spectrometry Nature communications High 31316063
2020 TEX264 forms a complex with p97 ATPase and SPRTN metalloprotease; TEX264 recognizes unmodified and SUMO1-modified TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN; TEX264 localizes to the nuclear periphery and associates with DNA replication forks. Co-IP, proximity ligation assay, siRNA knockdown, TOP1cc assay, replication fork association by iPOND Nature communications High 32152270
2020 ATM/ATR phosphorylates and activates the deubiquitinase VCPIP1/VCIP135 in response to DPC induction; VCPIP1 then deubiquitinates SPRTN to promote its chromatin relocalization; subsequent acetylation of SPRTN promotes its relocation to sites of chromatin damage and DPC repair. In vitro deubiquitylation assay, Co-IP, chromatin fractionation, kinase assay, mouse knockout model with aging phenotype Molecular cell High 32649882
2021 Monoubiquitylation of SPRTN (induced in an E3 ligase-independent manner) triggers autocatalytic self-cleavage in trans and primes SPRTN for proteasomal degradation; the deubiquitylase USP7 antagonizes this negative regulation of SPRTN in the presence of DPCs. In vitro ubiquitylation/deubiquitylation assay, autocatalytic cleavage assay, co-IP, chromatin fractionation, proteasome inhibition Nucleic acids research High 33348378
2021 USP11 deubiquitinase interacts with SPRTN and cleaves monoubiquitinated SPRTN both in cells and in vitro; USP11 depletion impairs SPRTN deubiquitination, promotes SPRTN autocatalysis, and causes accumulation of unrepaired DPCs. Co-IP, in vitro deubiquitylation assay, siRNA knockdown, DPC quantification assay The Journal of biological chemistry Medium 33567341
2021 DPC ubiquitylation recruits SPRTN to repair sites; DPC SUMOylation prevents DNA double-strand break formation and channels DPC repair toward SPRTN proteolysis rather than homologous recombination, preventing deleterious genomic rearrangements. Cellular DPC repair assays, siRNA knockdown, SUMO/ubiquitin pathway inhibition, HR assays, genome instability markers Cell reports Medium 34879279
2022 p97/VCP (with adaptor Ufd1-Npl4) unfolds polyubiquitinated DPCs and thereby enables SPRTN to degrade tightly-folded crosslinked proteins that SPRTN alone cannot cleave; this cooperation was biochemically reconstituted with purified components. In vitro reconstitution with purified p97, Ufd1-Npl4, SPRTN, and fluorescent reporter DPC; unfolding and proteolysis assays The Journal of biological chemistry High 35469923
2021 SPRTN is recruited to trapped PARP1-DNA complexes (DPCs) in S-phase; SPRTN-deficient cells show hypersensitivity to PARP trappers, delayed clearance of trapped PARP1, increased replication fork stalling, and SPRTN is deubiquitinated upon trapping and is epistatic with TLS in response to talazoparib. Co-IP (SPRTN-PARP1), nuclear foci colocalization with CDC45, DPC clearance assay, replication fork assay, epistasis with TLS, SPRTN-deficient cells Nucleic acids research Medium 34551432
2023 SPRTN has an unexpected role in global-genome DPC repair (independent of replication-coupled detection); replication-independent DPC cleavage by SPRTN requires SUMO-targeted ubiquitylation of the protein adduct. Defective ubiquitin binding of SPRTN patient variants compromises global-genome DPC repair. PxP (Purification of x-linked Proteins) technique, engineered patient-variant cell lines, SUMO/ubiquitin pathway manipulation, DPC quantification Nature communications High 36681662
2025 DPC polyubiquitylation allosterically activates SPRTN via direct binding of ubiquitin to SPRTN's protease domain (distinct from known UBZ domain), promoting an open, active conformation; mutation of interfacial residues prevents allosteric activation and causes genomic instability and cell cycle defects. In vitro DPC repair reconstitution with SUMO/ubiquitin modifications, protein structure prediction, MD simulations, NMR spectroscopy, site-directed mutagenesis, cellular genome instability assays Nature communications High 40691134
2025 The N-terminal SprT catalytic region of SPRTN contains a ubiquitin-binding domain (USD, Ubiquitin Interface of SprT Domain) that binds ubiquitin chains in an avidity manner; USD-mediated ubiquitin chain binding leads to ~67-fold higher SPRTN protease activation toward polyubiquitinated DPCs compared to unmodified DPCs, while PCNA and monoUb-PCNA are poorly degraded. Biochemical binding assays, biophysical analysis, structural approaches, in vitro protease activity assay with polyubiquitinated DPC substrates, domain mutant analysis Nucleic acids research High 40685547
2021 SPRTN cleaves MRE11 between residues 559 and 580 to generate a C-terminally truncated MRE11 (TR-MRE11) that retains interaction with RAD50 and NBS1 but has dramatically reduced nuclease activity due to deficient DNA binding, leading to decreased HR repair and increased radiosensitivity. Tandem mass spectrometry, site-directed mutagenesis, in vitro nuclease assays, Co-IP, HR repair assays, clonogenic survival after irradiation Cell death & disease High 33558481
2023 SPRTN proteolytic degradation of DPCs is required upstream of DNA repair: SPRTN generates small cross-linked peptides on DNA, and this initial proteolytic step is required for downstream activation of DNA repair mediated through H2AX phosphorylation and accumulation of repair factors on chromatin. STAR assay (DPC purification/quantification), DPC repair kinetics, γH2AX immunoblot, chromatin fractionation, SPRTN-deficient cells Nucleic acids research Medium 36718861
2023 TDP1 and SPRTN cooperate in DPC repair: SPRTN proteolysis of histone H3-DPCs is required upstream of TDP1-mediated peptide removal; SPRTN and TDP1 function in different pathways for endogenous TOP1-DPCs, established in both human RPE1 cells and zebrafish embryos. Zebrafish knockout/knockdown model, human RPE1 cells, DPC quantification, genetic epistasis, histone H3-DPC and TOP1-DPC measurements Open biology Medium 37788708
2014 The Drosophila SPRTN ortholog maternal haploid (MH) recruits p97/TER94 to stalled replication forks via its SHP box in somatic cells, and accumulates specifically in the male pronucleus before the first S phase to maintain paternal DNA integrity during sperm chromatin decondensation. Drosophila genetics (maternal effect mutant), live imaging, immunostaining, UV sensitivity assays, replication fork localization Current biology : CB Medium 25242033
2014 SPRTN is essential for prevention of DNA replication stress during general DNA replication and for replication-related G2/M-checkpoint regulation in vivo; biallelic germline mutations in SPRTN cause a progeroid syndrome with genomic instability and early onset hepatocellular carcinoma (Ruijs-Aalfs syndrome). Patient-derived cell lines, in vitro characterization of SPRTN mutations, replication stress assays, checkpoint assays, genome instability markers Nature genetics High 25261934
2019 GCNA (germline-specific protein) physically interacts with Spartan/DVC-1 and Topoisomerase II in both mice and C. elegans, and GCNA mutants display genome maintenance defects including hypersensitivity to TOP2 poison, supporting a role for GCNA in promoting resolution of TOP2 DPCs. Co-IP (GCNA-Spartan, GCNA-TOP2), colocalization on condensed chromosomes, TOP2 poison sensitivity assays, mouse and C. elegans genetics Developmental cell Medium 31839538
2019 SPRTN interacts with GRP78, the ER stress sensor; SPRTN levels decrease during ER stress, and SPRTN-depleted cells show increased sensitivity to ER stress, suggesting a functional role for SPRTN in the ER stress/unfolded protein response. Pull-down assay, Co-IP, RNA sequencing, comet assay, mitotic index Cancer gene therapy Low 38086993
2026 PARP1/2 sense DPCs and modify them with poly(ADP-ribose) (PAR) to promote SPRTN-dependent repair; SPRTN contains a Nudix homology domain (NHD) that mediates direct non-covalent PAR binding; mutation of NHD leads to sustained DPCs; single-molecule analysis shows PARP1 activity significantly increases SPRTN binding to DPCs. Single-molecule analysis, PAR binding assay, domain mutant (NHD) functional assay, DPC quantification, PARP1/2 inhibition bioRxivpreprint Medium 41542513

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Molecular cell 203 27871366
2016 Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN. Molecular cell 195 27871365
2014 Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nature genetics 173 25261934
2012 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. Nature structural & molecular biology 153 23042605
2018 Replication-Coupled DNA-Protein Crosslink Repair by SPRTN and the Proteasome in Xenopus Egg Extracts. Molecular cell 151 30595436
2016 SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks. eLife 139 27852435
2012 DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. Nature structural & molecular biology 122 23042607
2012 Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response. Molecular cell 116 22681887
2014 Spartan deficiency causes genomic instability and progeroid phenotypes. Nature communications 96 25501849
2017 Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis. Nucleic acids research 95 28199696
2020 TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nature communications 86 32152270
2012 Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. The Journal of biological chemistry 86 22902628
2012 Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance. Nucleic acids research 80 22987070
2017 DNA-dependent protease activity of human Spartan facilitates replication of DNA-protein crosslink-containing DNA. Nucleic acids research 77 28053116
2012 A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN study results. HIV clinical trials 76 22592092
2012 Spartan/C1orf124 is important to prevent UV-induced mutagenesis. Cell cycle (Georgetown, Tex.) 63 22894931
2012 Regulation of error-prone translesion synthesis by Spartan/C1orf124. Nucleic acids research 54 23254330
2019 Safety findings from Phase 3 lasmiditan studies for acute treatment of migraine: Results from SAMURAI and SPARTAN. Cephalalgia : an international journal of headache 51 31166697
2019 GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability. Developmental cell 48 31839538
2021 The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability. Cell reports 47 34879279
2020 Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging. Molecular cell 47 32649882
2020 DNA Structure-Specific Cleavage of DNA-Protein Crosslinks by the SPRTN Protease. Molecular cell 45 32853547
2019 Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan. Cell reports 45 30893605
2005 Structures of NADH and CH3-H4folate complexes of Escherichia coli methylenetetrahydrofolate reductase reveal a spartan strategy for a ping-pong reaction. Biochemistry 41 16114881
2013 DVC1-0101 to treat peripheral arterial disease: a Phase I/IIa open-label dose-escalation clinical trial. Molecular therapy : the journal of the American Society of Gene Therapy 40 23319060
2019 SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication. Nature communications 38 31316063
2014 The Spartan ortholog maternal haploid is required for paternal chromosome integrity in the Drosophila zygote. Current biology : CB 35 25242033
2021 A ubiquitin switch controls autocatalytic inactivation of the DNA-protein crosslink repair protease SPRTN. Nucleic acids research 29 33348378
2023 SPRTN patient variants cause global-genome DNA-protein crosslink repair defects. Nature communications 26 36681662
2021 Replication-dependent cytotoxicity and Spartan-mediated repair of trapped PARP1-DNA complexes. Nucleic acids research 24 34551432
2022 Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease. Frontiers in molecular biosciences 23 35782873
2021 USP11 mediates repair of DNA-protein cross-links by deubiquitinating SPRTN metalloprotease. The Journal of biological chemistry 21 33567341
2022 Ubiquitin-directed AAA+ ATPase p97/VCP unfolds stable proteins crosslinked to DNA for proteolysis by SPRTN. The Journal of biological chemistry 20 35469923
2022 Cross-species incompatibility between a DNA satellite and the Drosophila Spartan homolog poisons germline genome integrity. Current biology : CB 20 35643081
2020 Function and evolution of the DNA-protein crosslink proteases Wss1 and SPRTN. DNA repair 20 32058279
2002 Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan Sprague-Dawley rats. Toxicology letters 18 12044704
2016 Crystal structure of human PCNA in complex with the PIP box of DVC1. Biochemical and biophysical research communications 16 27084448
2018 SPARTAN promotes genetic diversification of the immunoglobulin-variable gene locus in avian DT40 cells. DNA repair 15 29935364
2016 The DNA-binding box of human SPARTAN contributes to the targeting of Polη to DNA damage sites. DNA repair 13 27838458
2022 Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies. American journal of cancer research 11 35141028
2021 SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells. Cell death & disease 11 33558481
2019 Validation of the Spartan RXCYP2C19 Genotyping Assay Utilizing Blood Samples. Clinical and translational science 11 31664775
2023 Tyrosyl-DNA phosphodiesterase 1 (TDP1) and SPRTN protease repair histone 3 and topoisomerase 1 DNA-protein crosslinks in vivo. Open biology 10 37788708
2020 The Trinity of SPRTN Protease Regulation. Trends in biochemical sciences 9 33183910
2024 Sequence of Events in the Pathogenesis of Axial Spondyloarthritis: A Current Review-2023 SPARTAN Meeting Proceedings. Current rheumatology reports 8 38324125
2023 SPRTN-dependent DPC degradation precedes repair of damaged DNA: a proof of concept revealed by the STAR assay. Nucleic acids research 8 36718861
2021 SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators. Nucleic acids research 8 34500467
2019 A model of DNA damage response activation at stalled replication forks by SPRTN. Nature communications 6 31831745
2016 Improved quality of life in patients with no-option critical limb ischemia undergoing gene therapy with DVC1-0101. Scientific reports 6 27418463
2024 Year in Review: Novel Insights in the Pathogenesis of Spondyloarthritis - SPARTAN 2024 Annual Meeting Proceedings. Current rheumatology reports 5 39731620
2024 Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial. European journal of cancer (Oxford, England : 1990) 4 39243730
2024 Prior Local Therapy and First-Line Apalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of the SPARTAN Randomized Clinical Trial. JAMA network open 3 39405060
2022 SPRTN and TDP1/TDP2 Independently Suppress 5-Aza-2'-deoxycytidine-Induced Genomic Instability in Human TK6 Cell Line. Chemical research in toxicology 3 36282523
2025 Spondyloarthritis Research and Treatment Network (SPARTAN) Clinical and Imaging Year in Review 2024. Current rheumatology reports 2 40591037
2025 The dual ubiquitin binding mode of SPRTN secures rapid spatiotemporal proteolysis of DNA-protein crosslinks. Nucleic acids research 2 40685547
2025 Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability. Nature communications 2 40691134
2024 NMR Metabolite Profiling and Antioxidant Properties of Spartan, Jewels, Misty, and Camelia Blueberries. Journal of agricultural and food chemistry 2 39348468
2024 SPRTN metalloprotease participates in repair of ROS-mediated DNA-protein crosslinks. Scientific reports 2 39730693
2023 SPRTN is involved in hepatocellular carcinoma development through the ER stress response. Cancer gene therapy 2 38086993
2016 Extending and Applying Spartan to Perform Temporal Sensitivity Analyses for Predicting Changes in Influential Biological Pathways in Computational Models. IEEE/ACM transactions on computational biology and bioinformatics 2 26887007
2026 Statin use and outcomes in advanced prostate cancer:Secondary analysis of the SPARTAN trial. Urologic oncology 1 41654482
2024 The dual ubiquitin binding mode of SPRTN secures rapid spatiotemporal proteolysis of DNA-protein crosslinks. bioRxiv : the preprint server for biology 1 39651247
2026 PARP1 recruits SPRTN to DNA-protein crosslinks through a conserved poly-ADP-ribose binding domain. bioRxiv : the preprint server for biology 0 41542513
2026 SPARTAN: automated table detection and extraction from documents using advanced OpenCV heuristics and OCR techniques. Scientific reports 0 41882048
2021 [Apalutamide in patients with high-risk M0CRPC: data from the pivotal SPARTAN study and initial experience from a compassionate use program]. Aktuelle Urologie 0 33621992