{"gene":"SDE2","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2016,"finding":"Human SDE2 contains an N-terminal ubiquitin-like (UBL) fold that is cleaved at a diglycine motif via deubiquitinating enzyme activity, dependent on its PCNA-interacting peptide (PIP) box. The cleaved SDE2 C-terminal product negatively regulates UV-induced PCNA monoubiquitination and counteracts replication stress. The cleaved SDE2 fragment is subsequently degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner; failure to degrade SDE2 impairs S phase progression and cellular survival.","method":"Biochemical cleavage assays, PCNA interaction studies, genetic knockdown with S phase/survival readouts, ubiquitin E3 ligase functional assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemistry, genetics, cell biology) in a focused study with functional validation of both cleavage and degradation mechanisms","pmids":["27906959"],"is_preprint":false},{"year":2017,"finding":"Fission yeast and human SDE2 are translated as inactive precursor proteins with an N-terminal ubiquitin-fold domain linked by an invariant GGKGG motif to the C-terminal domain (Sde2-C). Ubiquitin-specific proteases Ubp5 and Ubp15 cleave after the first diglycine motif to generate a short-lived activated Sde2-C fragment with an N-terminal lysine, which is incorporated into spliceosomes. Sde2 facilitates spliceosomal association of the splicing factor Cactin/Cay1. Loss of Sde2 or defects in its activation lead to inefficient excision of selected introns from a subset of pre-mRNAs.","method":"Genetic screens, splicing reporter assays, biochemical processing assays, genetic interaction studies in S. pombe","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemistry, genetics, splicing assays) with identification of specific proteases and functional validation across yeast and human systems","pmids":["28947618"],"is_preprint":false},{"year":2019,"finding":"SDE2 cleavage after its UBL domain generates Lys-SDE2Ct bearing an N-terminal lysine residue, which is a short-lived substrate of the Arg/N-end rule pathway. UBR1 and UBR2 ubiquitin ligases mediate its degradation. The VCP/p97UFD1-NPL4 segregase cooperates with the Arg/N-end rule to promote phosphorylation-dependent, chromatin-associated Lys-SDE2Ct degradation upon UVC damage. Cells expressing the degradation-refractory K78V mutant (Val-SDE2Ct) fail to induce RPA phosphorylation and ssDNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery.","method":"Biochemical degradation assays, site-directed mutagenesis (K78V), RPA phosphorylation and ssDNA formation assays, genetic complementation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with biochemical assays and functional readouts identifying the N-end rule pathway components and mechanistic consequences","pmids":["30698750"],"is_preprint":false},{"year":2020,"finding":"SDE2 directly interacts with the fork protection complex (FPC) component TIMELESS (TIM) and enhances TIM stability, thereby aiding TIM localization to replication forks and coordinating replisome progression. Loss of SDE2 leads to impaired fork progression, stalled fork recovery, failure to activate CHK1 phosphorylation, and excessive MRE11-dependent degradation of reversed forks.","method":"Co-immunoprecipitation, protein stability assays, replication fork progression assays (DNA fiber), CHK1 phosphorylation analysis, genetic knockdown with fork degradation readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple functional assays (fork progression, CHK1 activation, fork protection), and epistasis with MRE11 in a single focused study","pmids":["33127907"],"is_preprint":false},{"year":2020,"finding":"Hypoxia promotes SDE2 polyubiquitination and proteasomal degradation via a mechanism independent of the Arg/N-end rule pathway and the CDT2 ubiquitin E3 ligase. SDE2 depletion or hypoxia potentiates DNA damage-induced PCNA monoubiquitination; overexpression of SDE2 protects against hypoxia-mediated regulation of PCNA monoubiquitination upon DNA damage.","method":"SILAC-based quantitative proteomics, ubiquitination assays, Western blot, SDE2 knockdown/overexpression with PCNA monoubiquitination readout","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assays and functional rescue experiments in a single lab, two orthogonal methods","pmids":["32743553"],"is_preprint":false},{"year":2021,"finding":"Human SDE2 functions as both an RNA-binding protein and a trans-acting adaptor protein. SDE2 depletion leads to widespread changes in alternative splicing, defects in ribosome biogenesis, and complete loss of cell viability, establishing SDE2 as essential for spliceosome and ribosome complex assembly and maturation in mammalian cells.","method":"RNA-binding protein assays, RNA-seq splicing analysis, ribosome biogenesis assays, SDE2 knockdown with viability readouts","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding demonstrated, combined with functional depletion phenotypes across two processes in a single lab study","pmids":["34365507"],"is_preprint":false},{"year":2022,"finding":"The NMR solution structure of the SDE2 SAP domain reveals a helix-extended loop-helix core consistent with canonical SAP folds, with a preference for ssDNA binding. The DNA interaction extends beyond the core SAP domain and is augmented by two conserved lysine residues in the C-terminal tail. Mutation of the SAP domain and extended C-terminus disrupts ssDNA binding and impairs TIM localization at replication forks, inhibiting efficient fork progression.","method":"NMR solution structure determination, mutagenesis, ssDNA binding assays, TIM localization (immunofluorescence), DNA fiber assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with mutagenesis and functional validation in a single focused study using multiple orthogonal methods","pmids":["35850305"],"is_preprint":false},{"year":2022,"finding":"In S. pombe, ubiquitin-fold-activated Sde2 (along with Cactin/Cay1 and Tls1) is specifically required for splicing of introns with a branchpoint-distant 3' splice site (large BP-3'ss spacing). These factors likely guide the 3'ss toward the spliceosome catalytic centre by folding the RNA between the BP and 3'ss.","method":"Splicing reporter assays using ura4 reporters in S. pombe mutant collections, genetic analyses, intron engineering (extending BP-3'ss spacing)","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic reporter assays and engineered intron variants confirming specificity, single lab","pmids":["36095128"],"is_preprint":false},{"year":2011,"finding":"In S. pombe, loss of Sde2 leads to derepression of a reporter gene near telomeric repeats, accumulation of noncoding telomeric transcripts, increased acetylated histone H3K14 and RNA polymerase II at telomeres, and reduced recruitment of the SHREC (SNF2 ATPase/histone deacetylase-containing) complex to telomeres. Sde2 genetically interacts with telomere regulators Taz1, Pof3, and Ccq1.","method":"Genetic deletion, telomeric silencing reporter assays, ChIP (H3K14ac and RNAPII), SHREC complex recruitment assays, genetic interaction analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with multiple chromatin readouts, single lab, consistent genetic interactions","pmids":["21333630"],"is_preprint":false},{"year":2025,"finding":"USP5 (ubiquitin-specific protease 5) is identified as the human deubiquitinating enzyme that cleaves SDE2 at the diglycine motif of its UBL domain to release the functional C-terminal domain (SDE2CT). SDE2UBL binds to USP5 with similar characteristics to ubiquitin but with reduced affinity, consistent with substrate mimicry. USP5 processes SDE2 both in vitro and in cells, confirmed by an activity-based probe engineered from SDE2UBL and a cellular reporter assay.","method":"Biochemical cleavage assays in vitro, proteomic profiling, mass spectrometry, activity-based probe, cellular reporter assay, biophysical binding analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution and multiple validation methods, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.23.655772"],"is_preprint":true},{"year":2026,"finding":"SDE2 binds to ATG5 and facilitates K48-linked ubiquitination and proteasomal degradation of ATG5, thereby suppressing autophagy and ferroptosis in multiple myeloma cells. Knockdown of SDE2 restores ATG5 levels, reactivates autophagy, and sensitizes MM cells to ferroptosis.","method":"Co-immunoprecipitation, ubiquitination assays, Western blot, SDE2 knockdown/overexpression in MM cell lines and xenograft models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assays identifying a new SDE2-ATG5 interaction axis, single lab with in vivo validation","pmids":["41666676"],"is_preprint":false}],"current_model":"Human SDE2 is synthesized as an inactive precursor with an N-terminal ubiquitin-like (UBL) domain; USP5 cleaves the UBL at a diglycine motif to release the active C-terminal domain (SDE2CT) bearing an N-terminal lysine, which is then a short-lived substrate degraded by the Arg/N-end rule (UBR1/UBR2) and CRL4CDT2 pathways in a PCNA-interaction- and damage-dependent manner; SDE2CT binds TIMELESS (TIM) via a SAP domain that also contacts ssDNA, stabilizes the fork protection complex at replication forks, and supports CHK1 activation and protection of stalled forks from MRE11-dependent degradation; additionally, SDE2 facilitates spliceosomal incorporation of Cactin for intron-specific pre-mRNA splicing (particularly BP-distant introns), acts as an RNA-binding protein required for ribosome biogenesis, and promotes K48-linked ubiquitination and degradation of ATG5 to suppress autophagy-ferroptosis."},"narrative":{"mechanistic_narrative":"SDE2 is a multifunctional protein synthesized as an inactive precursor whose N-terminal ubiquitin-like (UBL) domain is cleaved at a diglycine motif by deubiquitinating activity to release an active C-terminal product that governs the cellular response to replication stress and pre-mRNA splicing [PMID:27906959, PMID:28947618]. Cleavage generates an SDE2 C-terminal fragment bearing an N-terminal lysine that is intrinsically short-lived: it is degraded both by the CRL4CDT2 E3 ligase in a PCNA-interaction-, cell-cycle-, and DNA-damage-dependent manner and by the Arg/N-end rule pathway via UBR1/UBR2, with the VCP/p97-UFD1-NPL4 segregase promoting its chromatin-associated, damage-induced turnover [PMID:27906959, PMID:30698750]. This regulated degradation is functionally required, as a degradation-refractory mutant fails to support RPA phosphorylation, ssDNA formation, and PCNA-dependent damage bypass [PMID:30698750]. At replication forks, the C-terminal domain uses a SAP domain that binds ssDNA—an interaction extended and augmented by conserved C-terminal lysines—to stabilize the fork protection complex component TIMELESS, aiding its fork localization, supporting CHK1 activation, and protecting reversed forks from MRE11-dependent degradation [PMID:33127907, PMID:35850305]. Independently of its fork role, SDE2 acts in RNA metabolism: it facilitates spliceosomal incorporation of Cactin/Cay1 to drive excision of a specific subset of introns, particularly those with branchpoint-distant 3' splice sites, and functions as an RNA-binding adaptor essential for spliceosome and ribosome biogenesis and for cell viability [PMID:28947618, PMID:34365507, PMID:36095128]. SDE2 additionally promotes K48-linked ubiquitination and proteasomal degradation of ATG5, thereby suppressing autophagy and ferroptosis [PMID:41666676].","teleology":[{"year":2016,"claim":"Established that human SDE2 is not a constitutive protein but a self-processing UBL-fusion whose cleaved product controls the replication-stress response and is itself a regulated, degradation-controlled factor.","evidence":"Biochemical cleavage assays, PCNA interaction studies, and genetic knockdown with S phase/survival readouts, plus CRL4CDT2 E3 ligase assays in human cells","pmids":["27906959"],"confidence":"High","gaps":["Did not identify the protease performing UBL cleavage","Mechanism by which the cleaved fragment regulates PCNA monoubiquitination not resolved"]},{"year":2017,"claim":"Resolved the activation logic across yeast and human—cleavage after the diglycine motif yields a short-lived activated fragment—and revealed an unanticipated splicing function via spliceosomal recruitment of Cactin.","evidence":"Genetic screens, splicing reporter assays, and biochemical processing assays in S. pombe with human validation","pmids":["28947618"],"confidence":"High","gaps":["Identity of the human protease(s) responsible for cleavage not established","How splicing and replication-stress functions are partitioned unclear"]},{"year":2019,"claim":"Defined the degradation route of the activated fragment, showing its N-terminal lysine makes it an Arg/N-end rule substrate cleared with help from the VCP/p97 segregase, and that this turnover is required for damage bypass.","evidence":"Site-directed mutagenesis (K78V), biochemical degradation assays, and RPA phosphorylation/ssDNA formation readouts after UVC damage","pmids":["30698750"],"confidence":"High","gaps":["Relationship between Arg/N-end rule and CRL4CDT2 routes not fully reconciled","Phosphorylation site(s) triggering degradation not mapped"]},{"year":2020,"claim":"Identified the direct fork-protection effector of SDE2 by showing it binds and stabilizes TIMELESS to maintain the fork protection complex and guard reversed forks.","evidence":"Reciprocal Co-IP, protein stability assays, DNA fiber fork progression, CHK1 phosphorylation analysis, and MRE11 epistasis in human cells","pmids":["33127907"],"confidence":"High","gaps":["Structural basis of the SDE2-TIM interaction not defined here","Whether TIM stabilization requires SDE2 cleavage not addressed"]},{"year":2020,"claim":"Showed SDE2 abundance is environmentally tuned, as hypoxia drives its polyubiquitination and degradation through a route distinct from the Arg/N-end rule and CDT2, linking oxygen status to PCNA monoubiquitination control.","evidence":"SILAC quantitative proteomics, ubiquitination assays, and knockdown/overexpression with PCNA monoubiquitination readouts","pmids":["32743553"],"confidence":"Medium","gaps":["The E3 ligase mediating hypoxic degradation not identified","Single-lab biochemistry without orthogonal genetic validation"]},{"year":2021,"claim":"Broadened SDE2 from a splicing factor to an essential dual RNA-binding/adaptor protein required for both spliceosome and ribosome assembly and for viability in mammalian cells.","evidence":"RNA-binding assays, RNA-seq splicing analysis, ribosome biogenesis assays, and knockdown viability readouts","pmids":["34365507"],"confidence":"Medium","gaps":["Direct RNA targets and binding motif not defined","How the same protein coordinates splicing and ribosome biogenesis mechanistically unclear"]},{"year":2022,"claim":"Provided the structural and biochemical basis for fork function by solving the SAP domain and showing ssDNA binding, augmented by C-terminal lysines, is required for TIM localization and fork progression.","evidence":"NMR solution structure, mutagenesis, ssDNA binding assays, immunofluorescence TIM localization, and DNA fiber assays","pmids":["35850305"],"confidence":"High","gaps":["Whether ssDNA and TIM binding are competitive or cooperative not resolved","No full-length structure of the cleaved C-terminal domain"]},{"year":2022,"claim":"Refined the splicing specificity, demonstrating that activated Sde2 with Cactin/Cay1 and Tls1 is selectively needed for introns with branchpoint-distant 3' splice sites.","evidence":"ura4 splicing reporter assays and engineered intron variants with extended BP-3'ss spacing in S. pombe","pmids":["36095128"],"confidence":"Medium","gaps":["Direct demonstration of RNA folding between BP and 3'ss lacking","Conservation of this intron-class specificity in human cells not shown"]},{"year":2025,"claim":"Filled the long-standing gap of the activating protease, identifying USP5 as the human DUB that cleaves the SDE2 UBL via ubiquitin substrate mimicry to release the functional C-terminal domain.","evidence":"In vitro cleavage assays, mass spectrometry, an SDE2-UBL activity-based probe, cellular reporter, and biophysical binding analysis (preprint)","pmids":["bio_10.1101_2025.05.23.655772"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Whether USP5 accounts for all cellular SDE2 processing not established"]},{"year":2026,"claim":"Extended SDE2 into proteostasis control of cell death by showing it binds ATG5 and drives its K48-linked ubiquitination and degradation to suppress autophagy and ferroptosis.","evidence":"Reciprocal Co-IP, ubiquitination assays, and knockdown/overexpression in multiple myeloma cell lines and xenografts","pmids":["41666676"],"confidence":"Medium","gaps":["The E3 ligase SDE2 recruits to ATG5 not identified","Whether this function requires SDE2 cleavage or its RNA/fork roles unclear"]},{"year":null,"claim":"How SDE2's distinct activities—replication-fork protection, intron-specific splicing, ribosome biogenesis, and ATG5/autophagy control—are coordinated, and whether they share a common requirement for UBL cleavage and regulated degradation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking the RNA-metabolism and DNA-replication functions","Cross-talk between the multiple degradation pathways (CRL4CDT2, Arg/N-end rule, hypoxic) not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,5,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]}],"complexes":["spliceosome","fork protection complex"],"partners":["TIMELESS","USP5","PCNA","ATG5","CACTIN","UBR1","UBR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6IQ49","full_name":"Splicing regulator SDE2","aliases":["Replication stress response regulator SDE2"],"length_aa":451,"mass_kda":49.7,"function":"Inhibits translesion DNA synthesis by preventing monoubiquitination of PCNA, this is necessary to counteract damage due to ultraviolet light-induced replication stress (PubMed:27906959). SDE2 is cleaved following PCNA binding, and its complete degradation is necessary to allow S-phase progression following DNA damage (PubMed:27906959) Plays a role in pre-mRNA splicing by facilitating excision of relatively short introns featuring weak 3'-splice sites (ss) and high GC content (PubMed:34365507). May recruit CACTIN to the spliceosome (By similarity) Plays a role in ribosome biogenesis by enabling SNORD3- and SNORD118-dependent cleavage of the 47S rRNA precursor (PubMed:34365507). Binds ncRNA (non-coding RNA) including the snoRNAs SNORD3 and SNORD118 (PubMed:34365507)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6IQ49/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SDE2","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SDE2","total_profiled":1310},"omim":[{"mim_id":"620743","title":"SDE2 TELOMERE MAINTENANCE HOMOLOG; SDE2","url":"https://www.omim.org/entry/620743"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SDE2"},"hgnc":{"alias_symbol":["FLJ35382"],"prev_symbol":["C1orf55"]},"alphafold":{"accession":"Q6IQ49","domains":[{"cath_id":"3.10.20.30","chopping":"7-75","consensus_level":"high","plddt":84.6099,"start":7,"end":75},{"cath_id":"-","chopping":"394-442","consensus_level":"high","plddt":88.4455,"start":394,"end":442},{"cath_id":"1.20.5","chopping":"94-146","consensus_level":"medium","plddt":91.1179,"start":94,"end":146}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IQ49","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IQ49-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IQ49-F1-predicted_aligned_error_v6.png","plddt_mean":65.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SDE2","jax_strain_url":"https://www.jax.org/strain/search?query=SDE2"},"sequence":{"accession":"Q6IQ49","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6IQ49.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6IQ49/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IQ49"}},"corpus_meta":[{"pmid":"33127907","id":"PMC_33127907","title":"SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33127907","citation_count":39,"is_preprint":false},{"pmid":"28947618","id":"PMC_28947618","title":"Sde2 is an intron-specific pre-mRNA splicing regulator activated by ubiquitin-like processing.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28947618","citation_count":36,"is_preprint":false},{"pmid":"27906959","id":"PMC_27906959","title":"PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27906959","citation_count":35,"is_preprint":false},{"pmid":"29680649","id":"PMC_29680649","title":"An initiator codon mutation in SDE2 causes recessive embryonic lethality in Holstein cattle.","date":"2018","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/29680649","citation_count":25,"is_preprint":false},{"pmid":"21333630","id":"PMC_21333630","title":"Sde2: a novel nuclear protein essential for telomeric silencing and genomic stability in Schizosaccharomyces pombe.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21333630","citation_count":22,"is_preprint":false},{"pmid":"30698750","id":"PMC_30698750","title":"Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30698750","citation_count":18,"is_preprint":false},{"pmid":"34365507","id":"PMC_34365507","title":"SDE2 is an essential gene required for ribosome biogenesis and the regulation of alternative splicing.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34365507","citation_count":16,"is_preprint":false},{"pmid":"35850305","id":"PMC_35850305","title":"Extended DNA-binding interfaces beyond the canonical SAP domain contribute to the function of replication stress regulator SDE2 at DNA replication forks.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35850305","citation_count":15,"is_preprint":false},{"pmid":"32743553","id":"PMC_32743553","title":"Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells.","date":"2020","source":"NAR cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32743553","citation_count":11,"is_preprint":false},{"pmid":"36095128","id":"PMC_36095128","title":"Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36095128","citation_count":8,"is_preprint":false},{"pmid":"33553608","id":"PMC_33553608","title":"Roles of SDE2 and TIMELESS at active and stalled DNA replication forks.","date":"2020","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33553608","citation_count":5,"is_preprint":false},{"pmid":"31560480","id":"PMC_31560480","title":"Missense mutation in SDE2 gene - new lethal defect transmitted into Polish Holstein-Friesian cattle.","date":"2019","source":"Polish journal of veterinary sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31560480","citation_count":2,"is_preprint":false},{"pmid":"41666676","id":"PMC_41666676","title":"Inhibition of SDE2 promotes autophagy-dependent ferroptosis in multiple myeloma.","date":"2026","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/41666676","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.23.655772","title":"A Proteolytic Switch: USP5 controls SDE2 function via UBL-directed cleavage","date":"2025-05-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.23.655772","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8457,"output_tokens":3310,"usd":0.037511,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10804,"output_tokens":3782,"usd":0.074285,"stage2_stop_reason":"end_turn"},"total_usd":0.111796,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Human SDE2 contains an N-terminal ubiquitin-like (UBL) fold that is cleaved at a diglycine motif via deubiquitinating enzyme activity, dependent on its PCNA-interacting peptide (PIP) box. The cleaved SDE2 C-terminal product negatively regulates UV-induced PCNA monoubiquitination and counteracts replication stress. The cleaved SDE2 fragment is subsequently degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner; failure to degrade SDE2 impairs S phase progression and cellular survival.\",\n      \"method\": \"Biochemical cleavage assays, PCNA interaction studies, genetic knockdown with S phase/survival readouts, ubiquitin E3 ligase functional assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemistry, genetics, cell biology) in a focused study with functional validation of both cleavage and degradation mechanisms\",\n      \"pmids\": [\"27906959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fission yeast and human SDE2 are translated as inactive precursor proteins with an N-terminal ubiquitin-fold domain linked by an invariant GGKGG motif to the C-terminal domain (Sde2-C). Ubiquitin-specific proteases Ubp5 and Ubp15 cleave after the first diglycine motif to generate a short-lived activated Sde2-C fragment with an N-terminal lysine, which is incorporated into spliceosomes. Sde2 facilitates spliceosomal association of the splicing factor Cactin/Cay1. Loss of Sde2 or defects in its activation lead to inefficient excision of selected introns from a subset of pre-mRNAs.\",\n      \"method\": \"Genetic screens, splicing reporter assays, biochemical processing assays, genetic interaction studies in S. pombe\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemistry, genetics, splicing assays) with identification of specific proteases and functional validation across yeast and human systems\",\n      \"pmids\": [\"28947618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SDE2 cleavage after its UBL domain generates Lys-SDE2Ct bearing an N-terminal lysine residue, which is a short-lived substrate of the Arg/N-end rule pathway. UBR1 and UBR2 ubiquitin ligases mediate its degradation. The VCP/p97UFD1-NPL4 segregase cooperates with the Arg/N-end rule to promote phosphorylation-dependent, chromatin-associated Lys-SDE2Ct degradation upon UVC damage. Cells expressing the degradation-refractory K78V mutant (Val-SDE2Ct) fail to induce RPA phosphorylation and ssDNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery.\",\n      \"method\": \"Biochemical degradation assays, site-directed mutagenesis (K78V), RPA phosphorylation and ssDNA formation assays, genetic complementation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with biochemical assays and functional readouts identifying the N-end rule pathway components and mechanistic consequences\",\n      \"pmids\": [\"30698750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SDE2 directly interacts with the fork protection complex (FPC) component TIMELESS (TIM) and enhances TIM stability, thereby aiding TIM localization to replication forks and coordinating replisome progression. Loss of SDE2 leads to impaired fork progression, stalled fork recovery, failure to activate CHK1 phosphorylation, and excessive MRE11-dependent degradation of reversed forks.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, replication fork progression assays (DNA fiber), CHK1 phosphorylation analysis, genetic knockdown with fork degradation readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple functional assays (fork progression, CHK1 activation, fork protection), and epistasis with MRE11 in a single focused study\",\n      \"pmids\": [\"33127907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hypoxia promotes SDE2 polyubiquitination and proteasomal degradation via a mechanism independent of the Arg/N-end rule pathway and the CDT2 ubiquitin E3 ligase. SDE2 depletion or hypoxia potentiates DNA damage-induced PCNA monoubiquitination; overexpression of SDE2 protects against hypoxia-mediated regulation of PCNA monoubiquitination upon DNA damage.\",\n      \"method\": \"SILAC-based quantitative proteomics, ubiquitination assays, Western blot, SDE2 knockdown/overexpression with PCNA monoubiquitination readout\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assays and functional rescue experiments in a single lab, two orthogonal methods\",\n      \"pmids\": [\"32743553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human SDE2 functions as both an RNA-binding protein and a trans-acting adaptor protein. SDE2 depletion leads to widespread changes in alternative splicing, defects in ribosome biogenesis, and complete loss of cell viability, establishing SDE2 as essential for spliceosome and ribosome complex assembly and maturation in mammalian cells.\",\n      \"method\": \"RNA-binding protein assays, RNA-seq splicing analysis, ribosome biogenesis assays, SDE2 knockdown with viability readouts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding demonstrated, combined with functional depletion phenotypes across two processes in a single lab study\",\n      \"pmids\": [\"34365507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The NMR solution structure of the SDE2 SAP domain reveals a helix-extended loop-helix core consistent with canonical SAP folds, with a preference for ssDNA binding. The DNA interaction extends beyond the core SAP domain and is augmented by two conserved lysine residues in the C-terminal tail. Mutation of the SAP domain and extended C-terminus disrupts ssDNA binding and impairs TIM localization at replication forks, inhibiting efficient fork progression.\",\n      \"method\": \"NMR solution structure determination, mutagenesis, ssDNA binding assays, TIM localization (immunofluorescence), DNA fiber assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with mutagenesis and functional validation in a single focused study using multiple orthogonal methods\",\n      \"pmids\": [\"35850305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In S. pombe, ubiquitin-fold-activated Sde2 (along with Cactin/Cay1 and Tls1) is specifically required for splicing of introns with a branchpoint-distant 3' splice site (large BP-3'ss spacing). These factors likely guide the 3'ss toward the spliceosome catalytic centre by folding the RNA between the BP and 3'ss.\",\n      \"method\": \"Splicing reporter assays using ura4 reporters in S. pombe mutant collections, genetic analyses, intron engineering (extending BP-3'ss spacing)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic reporter assays and engineered intron variants confirming specificity, single lab\",\n      \"pmids\": [\"36095128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In S. pombe, loss of Sde2 leads to derepression of a reporter gene near telomeric repeats, accumulation of noncoding telomeric transcripts, increased acetylated histone H3K14 and RNA polymerase II at telomeres, and reduced recruitment of the SHREC (SNF2 ATPase/histone deacetylase-containing) complex to telomeres. Sde2 genetically interacts with telomere regulators Taz1, Pof3, and Ccq1.\",\n      \"method\": \"Genetic deletion, telomeric silencing reporter assays, ChIP (H3K14ac and RNAPII), SHREC complex recruitment assays, genetic interaction analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with multiple chromatin readouts, single lab, consistent genetic interactions\",\n      \"pmids\": [\"21333630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP5 (ubiquitin-specific protease 5) is identified as the human deubiquitinating enzyme that cleaves SDE2 at the diglycine motif of its UBL domain to release the functional C-terminal domain (SDE2CT). SDE2UBL binds to USP5 with similar characteristics to ubiquitin but with reduced affinity, consistent with substrate mimicry. USP5 processes SDE2 both in vitro and in cells, confirmed by an activity-based probe engineered from SDE2UBL and a cellular reporter assay.\",\n      \"method\": \"Biochemical cleavage assays in vitro, proteomic profiling, mass spectrometry, activity-based probe, cellular reporter assay, biophysical binding analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution and multiple validation methods, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.23.655772\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SDE2 binds to ATG5 and facilitates K48-linked ubiquitination and proteasomal degradation of ATG5, thereby suppressing autophagy and ferroptosis in multiple myeloma cells. Knockdown of SDE2 restores ATG5 levels, reactivates autophagy, and sensitizes MM cells to ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Western blot, SDE2 knockdown/overexpression in MM cell lines and xenograft models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assays identifying a new SDE2-ATG5 interaction axis, single lab with in vivo validation\",\n      \"pmids\": [\"41666676\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human SDE2 is synthesized as an inactive precursor with an N-terminal ubiquitin-like (UBL) domain; USP5 cleaves the UBL at a diglycine motif to release the active C-terminal domain (SDE2CT) bearing an N-terminal lysine, which is then a short-lived substrate degraded by the Arg/N-end rule (UBR1/UBR2) and CRL4CDT2 pathways in a PCNA-interaction- and damage-dependent manner; SDE2CT binds TIMELESS (TIM) via a SAP domain that also contacts ssDNA, stabilizes the fork protection complex at replication forks, and supports CHK1 activation and protection of stalled forks from MRE11-dependent degradation; additionally, SDE2 facilitates spliceosomal incorporation of Cactin for intron-specific pre-mRNA splicing (particularly BP-distant introns), acts as an RNA-binding protein required for ribosome biogenesis, and promotes K48-linked ubiquitination and degradation of ATG5 to suppress autophagy-ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SDE2 is a multifunctional protein synthesized as an inactive precursor whose N-terminal ubiquitin-like (UBL) domain is cleaved at a diglycine motif by deubiquitinating activity to release an active C-terminal product that governs the cellular response to replication stress and pre-mRNA splicing [#0, #1]. Cleavage generates an SDE2 C-terminal fragment bearing an N-terminal lysine that is intrinsically short-lived: it is degraded both by the CRL4CDT2 E3 ligase in a PCNA-interaction-, cell-cycle-, and DNA-damage-dependent manner and by the Arg/N-end rule pathway via UBR1/UBR2, with the VCP/p97-UFD1-NPL4 segregase promoting its chromatin-associated, damage-induced turnover [#0, #2]. This regulated degradation is functionally required, as a degradation-refractory mutant fails to support RPA phosphorylation, ssDNA formation, and PCNA-dependent damage bypass [#2]. At replication forks, the C-terminal domain uses a SAP domain that binds ssDNA—an interaction extended and augmented by conserved C-terminal lysines—to stabilize the fork protection complex component TIMELESS, aiding its fork localization, supporting CHK1 activation, and protecting reversed forks from MRE11-dependent degradation [#3, #6]. Independently of its fork role, SDE2 acts in RNA metabolism: it facilitates spliceosomal incorporation of Cactin/Cay1 to drive excision of a specific subset of introns, particularly those with branchpoint-distant 3' splice sites, and functions as an RNA-binding adaptor essential for spliceosome and ribosome biogenesis and for cell viability [#1, #5, #7]. SDE2 additionally promotes K48-linked ubiquitination and proteasomal degradation of ATG5, thereby suppressing autophagy and ferroptosis [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that human SDE2 is not a constitutive protein but a self-processing UBL-fusion whose cleaved product controls the replication-stress response and is itself a regulated, degradation-controlled factor.\",\n      \"evidence\": \"Biochemical cleavage assays, PCNA interaction studies, and genetic knockdown with S phase/survival readouts, plus CRL4CDT2 E3 ligase assays in human cells\",\n      \"pmids\": [\"27906959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the protease performing UBL cleavage\", \"Mechanism by which the cleaved fragment regulates PCNA monoubiquitination not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the activation logic across yeast and human—cleavage after the diglycine motif yields a short-lived activated fragment—and revealed an unanticipated splicing function via spliceosomal recruitment of Cactin.\",\n      \"evidence\": \"Genetic screens, splicing reporter assays, and biochemical processing assays in S. pombe with human validation\",\n      \"pmids\": [\"28947618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the human protease(s) responsible for cleavage not established\", \"How splicing and replication-stress functions are partitioned unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the degradation route of the activated fragment, showing its N-terminal lysine makes it an Arg/N-end rule substrate cleared with help from the VCP/p97 segregase, and that this turnover is required for damage bypass.\",\n      \"evidence\": \"Site-directed mutagenesis (K78V), biochemical degradation assays, and RPA phosphorylation/ssDNA formation readouts after UVC damage\",\n      \"pmids\": [\"30698750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between Arg/N-end rule and CRL4CDT2 routes not fully reconciled\", \"Phosphorylation site(s) triggering degradation not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the direct fork-protection effector of SDE2 by showing it binds and stabilizes TIMELESS to maintain the fork protection complex and guard reversed forks.\",\n      \"evidence\": \"Reciprocal Co-IP, protein stability assays, DNA fiber fork progression, CHK1 phosphorylation analysis, and MRE11 epistasis in human cells\",\n      \"pmids\": [\"33127907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SDE2-TIM interaction not defined here\", \"Whether TIM stabilization requires SDE2 cleavage not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed SDE2 abundance is environmentally tuned, as hypoxia drives its polyubiquitination and degradation through a route distinct from the Arg/N-end rule and CDT2, linking oxygen status to PCNA monoubiquitination control.\",\n      \"evidence\": \"SILAC quantitative proteomics, ubiquitination assays, and knockdown/overexpression with PCNA monoubiquitination readouts\",\n      \"pmids\": [\"32743553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase mediating hypoxic degradation not identified\", \"Single-lab biochemistry without orthogonal genetic validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened SDE2 from a splicing factor to an essential dual RNA-binding/adaptor protein required for both spliceosome and ribosome assembly and for viability in mammalian cells.\",\n      \"evidence\": \"RNA-binding assays, RNA-seq splicing analysis, ribosome biogenesis assays, and knockdown viability readouts\",\n      \"pmids\": [\"34365507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA targets and binding motif not defined\", \"How the same protein coordinates splicing and ribosome biogenesis mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the structural and biochemical basis for fork function by solving the SAP domain and showing ssDNA binding, augmented by C-terminal lysines, is required for TIM localization and fork progression.\",\n      \"evidence\": \"NMR solution structure, mutagenesis, ssDNA binding assays, immunofluorescence TIM localization, and DNA fiber assays\",\n      \"pmids\": [\"35850305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ssDNA and TIM binding are competitive or cooperative not resolved\", \"No full-length structure of the cleaved C-terminal domain\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the splicing specificity, demonstrating that activated Sde2 with Cactin/Cay1 and Tls1 is selectively needed for introns with branchpoint-distant 3' splice sites.\",\n      \"evidence\": \"ura4 splicing reporter assays and engineered intron variants with extended BP-3'ss spacing in S. pombe\",\n      \"pmids\": [\"36095128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of RNA folding between BP and 3'ss lacking\", \"Conservation of this intron-class specificity in human cells not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Filled the long-standing gap of the activating protease, identifying USP5 as the human DUB that cleaves the SDE2 UBL via ubiquitin substrate mimicry to release the functional C-terminal domain.\",\n      \"evidence\": \"In vitro cleavage assays, mass spectrometry, an SDE2-UBL activity-based probe, cellular reporter, and biophysical binding analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.23.655772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Whether USP5 accounts for all cellular SDE2 processing not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended SDE2 into proteostasis control of cell death by showing it binds ATG5 and drives its K48-linked ubiquitination and degradation to suppress autophagy and ferroptosis.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, and knockdown/overexpression in multiple myeloma cell lines and xenografts\",\n      \"pmids\": [\"41666676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase SDE2 recruits to ATG5 not identified\", \"Whether this function requires SDE2 cleavage or its RNA/fork roles unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SDE2's distinct activities—replication-fork protection, intron-specific splicing, ribosome biogenesis, and ATG5/autophagy control—are coordinated, and whether they share a common requirement for UBL cleavage and regulated degradation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking the RNA-metabolism and DNA-replication functions\", \"Cross-talk between the multiple degradation pathways (CRL4CDT2, Arg/N-end rule, hypoxic) not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"spliceosome\", \"fork protection complex\"],\n    \"partners\": [\"TIMELESS\", \"USP5\", \"PCNA\", \"ATG5\", \"Cactin\", \"UBR1\", \"UBR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}