{"gene":"SLFN11","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2012,"finding":"SLFN11 expression causally determines cancer cell death and cell cycle arrest in response to DNA-damaging agents (topoisomerase I/II inhibitors, alkylating agents, DNA synthesis inhibitors), as demonstrated by siRNA-mediated silencing in cells with endogenously high and low SLFN11 expression.","method":"siRNA knockdown, cell viability assays, cell cycle analysis across NCI-60 panel","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined cellular phenotype replicated across multiple cell lines and cancer types from two independent groups","pmids":["22927417"],"is_preprint":false},{"year":2015,"finding":"SLFN11 directly interacts with RPA1 and is recruited to sites of DNA damage in an RPA1-dependent manner; SLFN11 inhibits checkpoint maintenance and homologous recombination repair by promoting destabilization of the RPA-ssDNA complex, and the RPA1-binding ability of SLFN11 is required for its function in the DNA damage response.","method":"Co-immunoprecipitation, direct interaction assays, RPA1-binding mutants, HR repair assays, checkpoint maintenance assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction established, functional mutagenesis confirming RPA1-binding requirement, multiple orthogonal methods in one study","pmids":["26658330"],"is_preprint":false},{"year":2015,"finding":"EWS-FLI1 binds near the transcription start site of the SLFN11 promoter and acts as a positive transcriptional regulator of SLFN11 expression in Ewing sarcoma cells; ETS1 also acts as a positive regulator of SLFN11 expression in breast cancer cells.","method":"ChIP-seq, promoter-luciferase reporter assays, EWS-FLI1 knockdown and overexpression, ETS1 molecular experiments","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq plus promoter reporter assays plus gain/loss-of-function experiments, single lab but multiple orthogonal methods","pmids":["25779942"],"is_preprint":false},{"year":2016,"finding":"SLFN11 inactivation causes resistance to PARP inhibitors (talazoparib, olaparib) through an irreversible and lethal replication inhibition mechanism independent of ATR-mediated S-phase checkpoint; this resistance is not due to impaired drug penetration or activation of homologous recombination.","method":"Isogenic SLFN11-positive and -negative cell lines (CRISPR/shRNA), cell viability assays, xenograft models, genomic analyses","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple isogenic cell line pairs, in vivo validation, mechanistic exclusion of alternative resistance mechanisms","pmids":["27708213"],"is_preprint":false},{"year":2016,"finding":"SLFN11 epigenetic silencing via promoter CpG island hypermethylation is associated with resistance to platinum compounds; BRCA1-interacting DHX9 RNA helicase (RHA) was identified as a protein partner for SLFN11.","method":"DNA methylation microarray (NCI-60), co-immunoprecipitation for DHX9 interaction, in vitro validation of methylation-expression relationship","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP for DHX9 binding, methylation-expression link validated in vitro, single lab","pmids":["26625211"],"is_preprint":false},{"year":2017,"finding":"In vivo chemoresistance in small cell lung cancer is associated with marked deposition of H3K27me3 (placed by EZH2) within the SLFN11 gene body, inducing local chromatin condensation and epigenetic silencing of SLFN11.","method":"Patient-derived xenograft models of paired chemosensitive/chemoresistant SCLC, ChIP for H3K27me3, EZH2 inhibitor treatment","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo PDX models with ChIP evidence for H3K27me3 deposition at SLFN11 gene body, EZH2 inhibitor reversal, multiple models","pmids":["28196596"],"is_preprint":false},{"year":2018,"finding":"In response to replication stress, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3; SLFN11 selectively blocks fork progression while inducing chromatin opening across replication initiation sites; the ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for tight chromatin binding.","method":"Chromatin fractionation, co-immunoprecipitation with RPA1/MCM3/CDC45/PCNA, ATPase domain mutants, iPOND (isolation of proteins on nascent DNA), cell death assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including chromatin fractionation, nascent DNA pulldown, domain mutagenesis, replicated with different replication stress agents","pmids":["29395061"],"is_preprint":false},{"year":2018,"finding":"SLFN11 preferentially inhibits translation of ATR and ATM serine/threonine kinases upon DNA-damaging agent (DDA) treatment based on distinct codon usage; type II tRNAs (including all serine and leucine tRNAs) are cleaved in a SLFN11-dependent manner in response to DDAs; mRNAs with high TTA (Leu) codon usage such as ATR are most susceptible to translational suppression; specific attenuation of tRNA-Leu-TAA suffices to ablate ATR protein expression.","method":"Transcriptome analysis, polysome profiling, tRNA cleavage assays, specific tRNA transfection/depletion, immunoblotting for ATR/ATM protein levels","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical tRNA cleavage assays, codon-usage mechanistic link, rescue experiments with specific tRNA, multiple orthogonal methods","pmids":["30374083"],"is_preprint":false},{"year":2018,"finding":"Class I (but not class II) HDAC inhibitors (romidepsin, entinostat) strongly induce SLFN11 mRNA and protein expression in cancer cells lacking SLFN11, restoring sensitivity to DNA-damaging agents.","method":"HDAC inhibitor treatment panel, immunoblotting, SLFN11 isogenic cell lines, synergy assays with camptothecin","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — class I vs II HDAC inhibitor specificity established, isogenic cell lines used, validated in patient PBMCs, multiple cancer cell lines","pmids":["29391350"],"is_preprint":false},{"year":2019,"finding":"SLFN11 loss leads to sensitization of tumor cells to IFN-γ-mediated T cell killing; SLFN11 does not influence IFNGR signaling but couples IFNGR signaling to induction of the DNA damage response (DDR) in a context-dependent fashion; loss of SLFN11 reduces IFN-γ-mediated toxicity.","method":"Genome-wide haploid genetic screen in HAP1 cells, SLFN11 knockout validation, IFN-γ treatment assays, T cell co-culture killing assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen with functional validation in knockout cells, single lab, IFN-γ coupling mechanism not fully resolved at molecular level","pmids":["30753225"],"is_preprint":false},{"year":2020,"finding":"SLFN11 increases chromatin accessibility genome-wide at active promoters in response to replication stress and selectively activates transcription of immediate early genes (IEGs: JUN, FOS, EGR1, NFKB2, ATF3) and cell cycle arrest genes (CDKN1A/p21, GADD45); both chromatin remodeling and IEG activation require the putative ATPase/helicase activity of SLFN11.","method":"ATAC-seq (chromatin accessibility), RNA-seq, isogenic SLFN11 KO vs WT cells, ATPase mutants, treatment with CHK1 inhibitor and TOP1 inhibitor","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ATAC-seq and RNA-seq in isogenic cells plus ATPase mutant domain analysis, replicated across NCI-60 cell lines","pmids":["32209474"],"is_preprint":false},{"year":2021,"finding":"SLFN11 promotes CDT1 degradation by binding to DDB1 of the CUL4-CDT2 E3 ubiquitin ligase complex associated with replication forks, requiring the C-terminus and ATPase domain of SLFN11; this irreversibly arrests replication by degrading CDT1 in response to DNA damage. In SLFN11-KO cells, CDT1 degradation is retarded, enabling replication reactivation. An ATPase mutant (E669K) identified in TCGA contributes to chemoresistance.","method":"Genome-wide RNAi screen, Co-IP of SLFN11 with DDB1, CDT1 degradation assays, SLFN11 C-terminus and ATPase domain truncation/mutation analysis, clinical TCGA mutant validation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — unbiased screen plus Co-IP plus domain mutagenesis plus clinical mutant validation, multiple orthogonal methods","pmids":["33536335"],"is_preprint":false},{"year":2021,"finding":"SLFN11 promotes extensive fork degradation in FANCD2-deficient cells via MRE11 or DNA2 nucleases, dependent on SLFN11 ATPase activity; SLFN11 knockdown in FA cells improves survival upon treatment with interstrand crosslink inducers and reduces chromosome breakage.","method":"SLFN11 knockdown in FANCD2-deficient PD20 cells, FANCD2-/-SLFN11-/- HAP1 double knockout, DNA fiber assays for fork degradation, nuclease inhibitors (MRE11, DNA2), RAD51 foci analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — double knockout epistasis, DNA fiber analysis, ATPase domain requirement, nuclease dependency established, orthogonal methods","pmids":["32735670"],"is_preprint":false},{"year":2021,"finding":"SLFN11 inactivation leads to enhanced global protein ubiquitylation, endoplasmic reticulum stress, unfolded protein response (UPR), and protein aggregation; SLFN11 functions as a regulator of protein quality control and attenuator of ER stress/UPR, and SLFN11-KO cells are sensitized to the UBA1 inhibitor TAK-243.","method":"Drug screen (1,978 compounds), proteomic analysis with biotinylated mass spectrometry, RNAi screening, UPR transducer immunoblotting (PERK, p-eIF2α, p-IRE1, ATF6), global ubiquitylation assays in isogenic SLFN11-KO vs WT cells","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — unbiased screen plus multiple biochemical orthogonal methods plus proteomic analysis plus RNAi screen, single lab","pmids":["33863777"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of human SLFN11 determined in dimeric apoenzyme state, bound to tRNA, and in complex with single-stranded DNA; full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state; structural and biochemical studies reveal mechanism of endoribonuclease activity and suggest how SLFN11 may block stressed replication forks.","method":"Cryo-electron microscopy (cryo-EM), biochemical ATPase assays, tRNA binding assays, ssDNA binding assays, structure-guided mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with biochemical and mutagenesis validation, multiple substrate-bound states resolved","pmids":["36115853"],"is_preprint":false},{"year":2022,"finding":"HCMV protein RL1 recruits the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex to degrade SLFN11; SLFN11 potently restricts HCMV infection by inhibiting viral plaque formation and spread.","method":"Multiplexed tandem mass tag proteomics screens, identification of RL1-CRL4 complex by proteomics, viral plaque assays, SLFN11 functional restriction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — two orthogonal proteomic screens plus viral plaque assays, mechanism of degradation via CRL4 complex established","pmids":["35105802"],"is_preprint":false},{"year":2023,"finding":"SLFN11 deficiency in HCC cells promotes macrophage migration and M2-like polarization in a CCL2-dependent manner, which elevates PD-L1 expression in tumor cells via NF-κB pathway activation; mechanistically, SLFN11 suppresses the Notch pathway and CCL2 transcription by binding competitively with TRIM21 to the RRM2 domain of RBM10, thereby inhibiting TRIM21-mediated RBM10 degradation, stabilizing RBM10 and promoting NUMB exon 9 skipping.","method":"SLFN11 knockdown in HCC cells, co-culture systems, cytometry by time-of-flight, humanized orthotopic mouse model, Co-IP for SLFN11-RBM10-TRIM21 interactions, splicing analysis","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interactions plus in vivo model plus splicing analysis, single lab, complex mechanism with multiple steps","pmids":["36863689"],"is_preprint":false},{"year":2023,"finding":"The RNase domain function of SLFN11 is dispensable for its role in replication stress response (suppressing DNA damage tolerance, destabilizing stalled replication forks, perturbing RAD51 recruitment); the helicase domain is essential for fork degradation, which proceeds via DNA2 and MRE11 nucleases.","method":"RNase active-site mutants (critical residues) expressed in SLFN11-/- cells, DNA fiber assays, RAD51 foci analysis, nuclease inhibition (DNA2, MRE11)","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain-specific mutagenesis with functional readouts, distinguishes RNase from helicase domain requirements, multiple assays","pmids":["37469008"],"is_preprint":false},{"year":2023,"finding":"SLFN11 is recruited to chromatin at unscheduled re-replication sites induced by pevonedistat (neddylation/CRL inhibitor), which causes CDT1 supraphysiologic accumulation; SLFN11 blocks unscheduled re-replication induced by pevonedistat, and SLFN11-proficient cells are selectively killed.","method":"High-throughput drug screen (1,978 compounds) in isogenic SLFN11-proficient/-deficient cell pairs, chromatin fractionation, flow cytometry for re-replication, multiple cancer cell databases","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic cell screen plus chromatin recruitment assays plus multiple independent databases, single lab","pmids":["37216280"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of SLFN11 bound to tRNA-Leu and tRNA-Met reveal tRNA binding and cleavage mechanisms; phosphorylation at S219 and T230 regulates tRNA recognition and nuclease activity; phosphomimetic S753D mutant adopts a monomeric conformation with ATP binding but loses ssDNA binding and shows reduced ribonuclease activity; S753 phosphorylation site serves as a conformational switch regulating SLFN11 dimerization as well as ATP and ssDNA binding.","method":"Cryo-EM structural determination, phosphomimetic mutagenesis (S753D), biochemical assays (ATP binding, ssDNA binding, ribonuclease activity), conformational analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures combined with biochemical and mutagenesis validation, multiple substrate complexes resolved, phosphorylation regulation mechanistically established","pmids":["39627193"],"is_preprint":false},{"year":2025,"finding":"SLFN11 induces TP53-independent apoptosis through ribosome biogenesis (RiBi) impairment: upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility at rDNA genes; SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis; the Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for ssDNA binding (S753), and RNase sites (E209/E214) are all required.","method":"SLFN11-proficient and -deficient isogenic cells, rRNA synthesis assays, RNA Pol I ChIP, ATAC-seq at rDNA, MCL1 protein stability assays, domain mutagenesis (E669, K652, S753, E209/E214), extended across 34 cancer cell lines","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple domain mutants, mechanistic pathway from rRNA inhibition to MCL1 depletion to apoptosis, replicated across 34 cell lines, multiple orthogonal methods","pmids":["39909041"],"is_preprint":false},{"year":2025,"finding":"SLFN11-mediated tRNA-Leu(TAA) cleavage triggers ER stress and protein aggregate formation leading to cell death regulated by IRE1α; tRNA fragments generated by SLFN11 contribute to ER stress and cell death; SLFN11 regulates proteostasis by cleaving tRNAs, influencing ubiquitin-dependent proteolysis.","method":"SLFN11 knockout cells, tRNA-Leu(TAA) transfection rescue, proteomics, IRE1α inhibition, identification of tRNA cleavage sites in cells, ER stress markers","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — rescue by tRNA transfection, IRE1α pathway validation, tRNA cleavage site mapping, proteomic analysis, multiple orthogonal methods","pmids":["40808299"],"is_preprint":false},{"year":2025,"finding":"RPA exhaustion and single-stranded DNA exposure are the trigger for SLFN11 activation and cell death under heightened replication stress; USP1-WDR48 deubiquitinase complex positively modulates SLFN11 activation; rapid RPA exhaustion upon DNA polymerase α chemical inhibition activates SLFN11-dependent cell death; SLFN11 is the critical determinant of cisplatin sensitivity in PrimPol-deficient cells.","method":"CRISPR-based screens, PrimPol-deficient cell models, RPA depletion experiments, USP1-WDR48 co-IP/validation, DNA polymerase α inhibition, epistasis analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screens with epistasis validation, multiple orthogonal mechanistic approaches (RPA depletion, USP1-WDR48, DNA pol α), published in high-quality journal","pmids":["41514018"],"is_preprint":false},{"year":2025,"finding":"SLFN11 acts upon stalled replication forks to suppress efficient fork restart; in the absence of SLFN11, fork restart proceeds through RFWD3-PRIMPOL-mediated gapped DNA synthesis; SLFN11 antagonizes this pathway by disrupting recruitment of RFWD3 and PRIMPOL to stalled forks, requiring a functional ATPase domain and persistent fork localization but not tRNA hydrolysis or ssDNA binding.","method":"Single-molecule DNA fiber analysis, super-resolution microscopy, RFWD3 and PRIMPOL co-IP/recruitment assays, ATPase mutants, tRNA hydrolysis mutants, ssDNA binding mutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — single-molecule DNA fiber and super-resolution microscopy, domain-specific mutants, protein recruitment assays, multiple orthogonal methods","pmids":["41372167"],"is_preprint":false},{"year":2026,"finding":"RNF168 E3 ubiquitin ligase is required for SLFN11 ubiquitylation and chromatin association; ubiquitylation of SLFN11 within its middle linker domain (lysines 390, 391, and 429) with K27-linked polyubiquitin chains is essential for chromatin recruitment; DUB inhibitors drive ubiquitin-dependent SLFN11 chromatin recruitment at promoter regions without detectable DNA damage; both DUB inhibitor- and DNA damage-induced SLFN11 chromatin recruitment are suppressed by TAK-243 (UBA1 inhibitor), demonstrating ubiquitylation dependency.","method":"High-throughput imaging screen, Co-IP for ubiquitylation, RNF168 knockout validation, site-specific ubiquitylation mutants (K390/391/429), K27-linkage determination, TAK-243 suppression experiments","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical ubiquitylation mapping with specific lysine mutants, K27-linkage determination, RNF168 KO epistasis, chemical validation with TAK-243, preprint but comprehensive","pmids":["41929013"],"is_preprint":true},{"year":2020,"finding":"SLFN11 physically associates with ribosomal protein RPS4X and blocks the mTOR signaling pathway, thereby inhibiting HCC cell proliferation, migration, and invasion in vitro and impeding HCC growth and metastasis in vivo.","method":"Immunoprecipitation, LC-MS/MS, Co-IP, co-immunofluorescence, xenograft mouse models, SLFN11 overexpression/knockdown cell lines","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with mass spectrometry identification of RPS4X, in vivo xenograft validation, single lab","pmids":["32292519"],"is_preprint":false},{"year":2025,"finding":"SLFN11 specifically binds to the LINE-1 5' untranslated region and blocks RNA polymerase II recruitment, thereby suppressing LINE-1 transcription; SLFN11 promotes heterochromatinization at LINE-1 loci; the inhibitory activity requires the helicase domain.","method":"LINE-1 retrotransposition reporter assays, ChIP for SLFN11 binding to LINE-1 5'UTR, RNA Pol II recruitment assays, helicase domain mutants, heterochromatin markers","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin binding assays plus domain mutagenesis plus functional reporter assays, single lab, single paper","pmids":["40497966"],"is_preprint":false},{"year":2022,"finding":"SLFN11 knockout in GBM cells stimulates expression of NF-κB target genes, consistent with a negative regulatory role on the non-canonical NF-κB pathway; p21 (encoded by CDKN1A) is identified as a direct transcriptional target of NF-κB2 whose expression is stimulated by loss of SLFN11.","method":"CRISPR/Cas9 SLFN11 KO, NF-κB target gene expression analysis, orthotopic patient-derived xenograft model, stem cell marker analysis","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with transcriptional profiling and in vivo validation, single lab, NF-κB2-p21 link inferred from transcriptomics","pmids":["36382088"],"is_preprint":false},{"year":2026,"finding":"In renal cell carcinoma cells, SLFN11 significantly upregulates CSF2 (encoding GM-CSF) expression; SLFN11-positive RCC cells co-cultured with M0 macrophages secrete higher GM-CSF and promote M1 macrophage polarization; SLFN11 is inversely correlated with BRCA1 expression and promotes proteasomal degradation of BRCA1 protein in ccRCC cells.","method":"Transcriptome and proteome analysis of RCC cell lines, macrophage co-culture assays, GM-CSF quantification, multiplex immunofluorescence on patient samples, SLFN11 loss-of-function for BRCA1 levels","journal":"Anticancer research / Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — transcriptomic and proteomic identification plus co-culture functional assays plus patient tissue validation, single lab","pmids":["41760260","42260628"],"is_preprint":false}],"current_model":"SLFN11 is an interferon-inducible restriction factor that, upon replication stress, is recruited to stalled replication forks via RPA1-coated ssDNA (triggered by RPA exhaustion) in a manner requiring RNF168-mediated K27-linked polyubiquitylation at lysines 390/391/429; once at forks, its ATPase domain drives chromatin opening, suppresses RFWD3-PRIMPOL-mediated fork restart, promotes CDT1 degradation through the CUL4-DDB1-CDT2 E3 ligase, and causes irreversible replication arrest; in parallel, SLFN11 cleaves type II tRNAs (especially tRNA-Leu-TAA) to selectively suppress translation of ATR/ATM and disrupt proteostasis via ER stress/IRE1α and ribosome biogenesis impairment with MCL1 depletion, collectively inducing p53-independent apoptosis; its expression is epigenetically silenced by EZH2 (H3K27me3) and DNA methylation in ~50% of cancers, and is transcriptionally activated by ETS factors including EWS-FLI1, making it the dominant predictor of sensitivity to DNA-damaging chemotherapies and PARP inhibitors."},"narrative":{"mechanistic_narrative":"SLFN11 is a replication-stress effector and restriction factor whose expression causally determines cancer cell death in response to DNA-damaging agents and PARP inhibitors, making it the dominant predictor of chemosensitivity [PMID:22927417, PMID:27708213]. Upon replication stress, SLFN11 is recruited to stalled forks through direct binding to RPA1 and the MCM3 helicase subunit, and RPA exhaustion with single-stranded DNA exposure serves as the activating trigger, positively modulated by the USP1-WDR48 deubiquitinase complex [PMID:26658330, PMID:29395061, PMID:41514018]; chromatin recruitment requires RNF168-mediated K27-linked polyubiquitylation of SLFN11 at lysines 390/391/429 [PMID:41929013]. Once at forks, its ATPase/helicase domain drives genome-wide chromatin opening, blocks fork progression, and converts reversible arrest into irreversible replication inhibition [PMID:29395061, PMID:32209474]; mechanistically it suppresses RFWD3-PRIMPOL-mediated fork restart [PMID:41372167], promotes CDT1 degradation by binding DDB1 of the CUL4-CDT2 E3 ligase [PMID:33536335], and destabilizes the RPA-ssDNA complex to inhibit homologous recombination [PMID:26658330]. In parallel, SLFN11 functions as an endoribonuclease that cleaves type II tRNAs—especially tRNA-Leu(TAA)—to selectively suppress translation of ATR and ATM based on codon usage and to disrupt proteostasis via IRE1α-dependent ER stress [PMID:30374083, PMID:40808299], while replication-stress-driven impairment of ribosome biogenesis depletes the short-lived protein MCL1 to induce TP53-independent apoptosis [PMID:39909041]. SLFN11 expression is epigenetically silenced through EZH2-mediated H3K27me3 deposition and promoter CpG hypermethylation in chemoresistant tumors, and is transcriptionally activated by ETS factors including EWS-FLI1 [PMID:25779942, PMID:26625211, PMID:28196596]; class I HDAC inhibitors and EZH2 inhibitors can restore its expression and re-sensitize cells to DNA-damaging therapy [PMID:28196596, PMID:29391350]. Cryo-EM structures resolve SLFN11 as a dimer bound to tRNA and ssDNA in which full-length protein adopts an autoinhibited helicase state, with phosphorylation at S753 acting as a conformational switch governing dimerization, ATP and ssDNA binding [PMID:36115853, PMID:39627193].","teleology":[{"year":2012,"claim":"Established that SLFN11 is not a bystander biomarker but a causal determinant of whether cancer cells die in response to DNA-damaging agents, defining the central functional question for the gene.","evidence":"siRNA knockdown with viability and cell cycle readouts across the NCI-60 panel","pmids":["22927417"],"confidence":"High","gaps":["Did not define the molecular mechanism linking SLFN11 to death","No protein partners or biochemical activity identified"]},{"year":2015,"claim":"Identified the physical route by which SLFN11 senses DNA damage—direct RPA1 binding and RPA1-dependent recruitment—and showed it acts by destabilizing RPA-ssDNA to block HR and checkpoint maintenance.","evidence":"Co-IP, RPA1-binding mutants, HR and checkpoint assays","pmids":["26658330"],"confidence":"High","gaps":["Catalytic activity at forks not yet defined","Did not address how RPA-bound SLFN11 enforces irreversibility"]},{"year":2015,"claim":"Connected SLFN11 expression to transcriptional control by oncogenic ETS factors, explaining why expression varies across tumor types.","evidence":"ChIP-seq, promoter reporter, EWS-FLI1 and ETS1 gain/loss-of-function","pmids":["25779942"],"confidence":"High","gaps":["Did not address epigenetic silencing mechanisms","Scope limited to Ewing sarcoma and breast cancer contexts"]},{"year":2016,"claim":"Showed that SLFN11 loss—whether by inactivation or promoter hypermethylation—drives resistance to PARP inhibitors and platinum, establishing the clinical resistance axis and a candidate partner DHX9.","evidence":"Isogenic CRISPR/shRNA lines, xenografts, methylation microarray, DHX9 Co-IP","pmids":["27708213","26625211"],"confidence":"High","gaps":["DHX9 interaction rests on single Co-IP without functional validation","Mechanism of irreversible replication inhibition not yet resolved"]},{"year":2017,"claim":"Defined a chromatin-based silencing mechanism (EZH2/H3K27me3 over the gene body) driving in vivo chemoresistance and showed it is pharmacologically reversible.","evidence":"Chemosensitive/resistant SCLC PDX models, H3K27me3 ChIP, EZH2 inhibitor reversal","pmids":["28196596"],"confidence":"High","gaps":["Did not address relative contribution of methylation vs H3K27me3 across tumor types","Upstream signals recruiting EZH2 to SLFN11 unclear"]},{"year":2018,"claim":"Resolved the core fork-acting mechanism: SLFN11 binds stressed forks via RPA1/MCM3 and uses its ATPase domain to open chromatin and block forks, separating tight binding from catalytic execution.","evidence":"Chromatin fractionation, iPOND, Co-IP with RPA1/MCM3/CDC45/PCNA, ATPase mutants","pmids":["29395061"],"confidence":"High","gaps":["Substrate of the ATPase activity not defined","Did not show how chromatin opening enforces irreversibility"]},{"year":2018,"claim":"Uncovered a parallel translational arm—SLFN11-dependent type II tRNA cleavage selectively suppressing ATR/ATM via codon usage—revealing endoribonuclease activity as a distinct effector mechanism.","evidence":"Polysome profiling, tRNA cleavage assays, codon-usage analysis, specific tRNA depletion/rescue","pmids":["30374083"],"confidence":"High","gaps":["Relationship between RNase and fork activities not yet dissected","Structural basis of tRNA selectivity unknown"]},{"year":2018,"claim":"Demonstrated that class I HDAC inhibitors can re-induce SLFN11 in silenced cells, providing a second pharmacological strategy to restore chemosensitivity.","evidence":"HDAC inhibitor panel, isogenic cell lines, immunoblot, camptothecin synergy, patient PBMCs","pmids":["29391350"],"confidence":"High","gaps":["Direct chromatin mechanism of induction not mapped","Did not test combination durability in vivo"]},{"year":2019,"claim":"Linked SLFN11 to immune-mediated killing by coupling IFN-γ signaling to the DNA damage response, broadening its role beyond chemotherapy.","evidence":"Genome-wide haploid screen in HAP1, knockout validation, T cell co-culture killing","pmids":["30753225"],"confidence":"Medium","gaps":["Molecular coupling of IFNGR signaling to DDR not resolved","Single lab, context-dependent effect"]},{"year":2020,"claim":"Showed that SLFN11's ATPase-dependent chromatin remodeling extends to transcription, selectively activating immediate early and cell cycle arrest genes including CDKN1A and GADD45.","evidence":"ATAC-seq, RNA-seq in isogenic cells, ATPase mutants, CHK1/TOP1 inhibitor treatment","pmids":["32209474"],"confidence":"High","gaps":["Whether transcriptional activation contributes to cell death vs is a byproduct unclear","Direct chromatin targets of remodeling not enumerated"]},{"year":2020,"claim":"Reported an additional partner RPS4X and an mTOR-suppressive, growth-inhibitory role in HCC, extending SLFN11 function to translation/proliferation control.","evidence":"IP-LC-MS/MS, Co-IP, co-IF, xenografts, overexpression/knockdown","pmids":["32292519"],"confidence":"Medium","gaps":["RPS4X interaction not reciprocally validated against fork/RNase functions","Single lab, single tumor context"]},{"year":2021,"claim":"Identified CDT1 degradation via SLFN11 binding to DDB1 of the CUL4-CDT2 ligase as a concrete mechanism enforcing irreversible replication arrest, with a clinical ATPase mutant validating relevance.","evidence":"Genome-wide RNAi screen, SLFN11-DDB1 Co-IP, CDT1 degradation assays, domain mutants, TCGA E669K mutant","pmids":["33536335"],"confidence":"High","gaps":["How CDT1 loss couples to apoptosis not detailed","Relationship to chromatin opening mechanism unresolved"]},{"year":2021,"claim":"Established context-dependent fork degradation: in FANCD2-deficient cells SLFN11 drives MRE11/DNA2-mediated fork resection, defining a deleterious-genome-instability arm.","evidence":"Knockdown in PD20, FANCD2/SLFN11 double KO, DNA fiber assays, nuclease inhibitors, RAD51 foci","pmids":["32735670"],"confidence":"High","gaps":["Whether this pathway operates in FA-proficient cells unclear","ATPase substrate driving resection not identified"]},{"year":2021,"claim":"Revealed a proteostasis function—SLFN11 attenuates ER stress/UPR and global ubiquitylation, sensitizing its loss to UBA1 inhibition.","evidence":"1,978-compound screen, biotin proteomics, RNAi, UPR transducer immunoblots, ubiquitylation assays","pmids":["33863777"],"confidence":"High","gaps":["Mechanistic link between SLFN11 and UPR transducers not fully defined at the time","Did not connect to tRNA cleavage directly"]},{"year":2022,"claim":"Provided the first structural framework: cryo-EM of dimeric SLFN11 bound to tRNA and ssDNA, showing the helicase domain is autoinhibited and full-length protein does not hydrolyze ATP.","evidence":"Cryo-EM, ATPase/tRNA/ssDNA binding assays, structure-guided mutagenesis","pmids":["36115853"],"confidence":"High","gaps":["How autoinhibition is relieved in cells not resolved","Active conformation at forks not captured"]},{"year":2022,"claim":"Showed SLFN11 restricts HCMV and is targeted for degradation by viral RL1 via CRL4, establishing an antiviral restriction-factor role.","evidence":"Tandem mass tag proteomics, RL1-CRL4 identification, viral plaque assays","pmids":["35105802"],"confidence":"High","gaps":["Mechanism by which SLFN11 restricts viral replication not defined","Whether antiviral and fork functions share machinery unknown"]},{"year":2022,"claim":"Reported SLFN11 as a negative regulator of non-canonical NF-κB signaling, with NF-κB2-driven p21 induction upon loss, linking SLFN11 to transcriptional/immune programs in GBM.","evidence":"CRISPR KO, NF-κB target profiling, orthotopic PDX","pmids":["36382088"],"confidence":"Medium","gaps":["NF-κB2-p21 link inferred from transcriptomics, not direct","Single lab, mechanism of NF-κB suppression unclear"]},{"year":2023,"claim":"Dissected domain division of labor, showing the RNase domain is dispensable for the replication-stress response while the helicase domain is essential for fork degradation via DNA2/MRE11.","evidence":"RNase active-site mutants in SLFN11-/- cells, DNA fiber assays, RAD51 foci, nuclease inhibition","pmids":["37469008"],"confidence":"High","gaps":["Did not reconcile with cryo-EM finding of autoinhibited ATPase","Substrate of helicase domain still undefined"]},{"year":2023,"claim":"Extended the irreversible-arrest model to re-replication stress, showing SLFN11 is recruited to pevonedistat-induced re-replication sites and selectively kills proficient cells.","evidence":"1,978-compound isogenic screen, chromatin fractionation, flow cytometry, cancer databases","pmids":["37216280"],"confidence":"Medium","gaps":["Mechanism of re-replication block not detailed","Single lab"]},{"year":2023,"claim":"Described an immune-modulatory mechanism in HCC: SLFN11 stabilizes RBM10 by competing with TRIM21, altering NUMB splicing and suppressing CCL2/Notch to limit M2 polarization and PD-L1.","evidence":"Knockdown, co-culture, CyTOF, humanized orthotopic model, Co-IP, splicing analysis","pmids":["36863689"],"confidence":"Medium","gaps":["Multi-step mechanism from a single lab","Relationship of RBM10 binding to replication functions unclear"]},{"year":2024,"claim":"Resolved tRNA recognition/cleavage structurally and identified S753 phosphorylation as a conformational switch controlling dimerization, ATP and ssDNA binding, plus S219/T230 phosphoregulation of nuclease activity.","evidence":"Cryo-EM with tRNA-Leu/Met, phosphomimetic S753D, ATP/ssDNA/RNase assays","pmids":["39627193"],"confidence":"High","gaps":["Kinases/phosphatases controlling these sites not identified","How phospho-switch is timed during replication stress unknown"]},{"year":2025,"claim":"Integrated the death mechanism: replication-stress-driven ribosome biogenesis impairment depletes short-lived MCL1, producing TP53-independent apoptosis, with multiple domains required.","evidence":"Isogenic cells, rRNA synthesis assays, RNA Pol I ChIP, rDNA ATAC-seq, MCL1 stability, domain mutants across 34 lines","pmids":["39909041"],"confidence":"High","gaps":["How fork engagement triggers rRNA shutdown not fully mapped","Relative contribution of RiBi vs CDT1/tRNA arms to death unquantified"]},{"year":2025,"claim":"Connected the tRNA-cleavage arm to proteostasis collapse, showing tRNA-Leu(TAA) fragments drive IRE1α-dependent ER stress and aggregate-associated death.","evidence":"Knockout cells, tRNA-Leu(TAA) rescue, proteomics, IRE1α inhibition, cleavage-site mapping","pmids":["40808299"],"confidence":"High","gaps":["How tRNA fragments are sensed by IRE1α not defined","Crosstalk with the fork/RiBi arms unresolved"]},{"year":2025,"claim":"Defined the activating trigger—RPA exhaustion and ssDNA exposure—and a positive regulator USP1-WDR48, and showed SLFN11 antagonizes RFWD3-PRIMPOL-mediated fork restart through ATPase activity and persistent localization rather than tRNA hydrolysis or ssDNA binding.","evidence":"CRISPR screens, PrimPol-deficient models, RPA depletion, USP1-WDR48 validation, DNA pol α inhibition; DNA fiber and super-resolution with domain mutants","pmids":["41514018","41372167"],"confidence":"High","gaps":["How USP1-WDR48 modulates SLFN11 mechanistically unclear","Reconciliation of ssDNA-independent fork function with RPA-dependent recruitment incomplete"]},{"year":2026,"claim":"Identified the ubiquitin signal for chromatin recruitment: RNF168-dependent K27-linked polyubiquitylation at K390/391/429 is required, and recruitment is UBA1-dependent and inducible by DUB inhibitors even without DNA damage.","evidence":"High-throughput imaging screen, ubiquitylation Co-IP, RNF168 KO, site-specific lysine mutants, K27-linkage mapping, TAK-243 suppression (preprint)","pmids":["41929013"],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","How K27 chains are read for chromatin engagement unknown"]},{"year":2026,"claim":"Extended SLFN11's immune-microenvironment role to RCC, where it upregulates CSF2/GM-CSF promoting M1 polarization and promotes proteasomal BRCA1 degradation.","evidence":"Transcriptome/proteome, macrophage co-culture, GM-CSF quantification, multiplex IF, loss-of-function for BRCA1","pmids":["41760260","42260628"],"confidence":"Medium","gaps":["BRCA1 degradation mechanism not biochemically defined","Single tumor context, single lab"]},{"year":null,"claim":"How SLFN11's distinct effector arms—ATPase-driven fork block/CDT1 degradation, tRNA cleavage, ribosome biogenesis shutdown, and chromatin/transcriptional remodeling—are coordinated in time and which dominates the death decision in a given context remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model quantifying relative contributions of each arm","Cell-type determinants selecting one effector pathway over another unknown","Active in-cell conformation relative to the autoinhibited apo structure not captured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[7,14,19,21]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,14,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,19,26]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[6,10,11,17,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[7,21]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,10,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,20]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,6,12,17]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6,11,18,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,20,21]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,20,21]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[13,21,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,10,26]}],"complexes":[],"partners":["RPA1","MCM3","DDB1","DHX9","RPS4X","RBM10","USP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z7L1","full_name":"Schlafen family member 11","aliases":[],"length_aa":901,"mass_kda":102.8,"function":"Inhibitor of DNA replication that promotes cell death in response to DNA damage (PubMed:22927417, PubMed:26658330, PubMed:29395061). Acts as a guardian of the genome by killing cells with defective replication (PubMed:29395061). Persistently blocks stressed replication forks by opening chromatin across replication initiation sites at stressed replication forks, possibly leading to unwind DNA ahead of the MCM helicase and block fork progression, ultimately leading to cell death (PubMed:29395061). Upon DNA damage, inhibits translation of ATR or ATM based on distinct codon usage without disrupting early DNA damage response signaling (PubMed:30374083). Antiviral restriction factor with manganese-dependent type II tRNA endoribonuclease (PubMed:36115853). A single tRNA molecule is bound and cleaved by the SLFN11 dimer (PubMed:36115853). Specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1) by acting as a specific inhibitor of the synthesis of retroviruses encoded proteins in a codon-usage-dependent manner (PubMed:23000900). Impairs the replication of human cytomegalovirus (HCMV) and some Flaviviruses (PubMed:35105802, PubMed:36115853). Exploits the unique viral codon bias towards A/T nucleotides (PubMed:23000900). Also acts as an interferon (IFN)-induced antiviral protein which acts as an inhibitor of retrovirus protein synthesis (PubMed:23000900)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q7Z7L1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLFN11","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLFN11","total_profiled":1310},"omim":[{"mim_id":"614958","title":"SCHLAFEN FAMILY, MEMBER 14; SLFN14","url":"https://www.omim.org/entry/614958"},{"mim_id":"614957","title":"SCHLAFEN FAMILY, MEMBER 13; SLFN13","url":"https://www.omim.org/entry/614957"},{"mim_id":"614956","title":"SCHLAFEN FAMILY, MEMBER 12-LIKE; SLFN12L","url":"https://www.omim.org/entry/614956"},{"mim_id":"614955","title":"SCHLAFEN FAMILY, MEMBER 12; SLFN12","url":"https://www.omim.org/entry/614955"},{"mim_id":"614953","title":"SCHLAFEN FAMILY, MEMBER 11; SLFN11","url":"https://www.omim.org/entry/614953"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLFN11"},"hgnc":{"alias_symbol":["FLJ34922"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z7L1","domains":[{"cath_id":"3.30.110","chopping":"11-108","consensus_level":"high","plddt":91.44,"start":11,"end":108},{"cath_id":"3.30.950","chopping":"134-156_191-325","consensus_level":"high","plddt":90.5415,"start":134,"end":325},{"cath_id":"-","chopping":"391-529_537-558","consensus_level":"high","plddt":89.6815,"start":391,"end":558},{"cath_id":"3.40.50.300","chopping":"578-733","consensus_level":"high","plddt":92.2292,"start":578,"end":733},{"cath_id":"3.40.50.300","chopping":"777-897","consensus_level":"high","plddt":89.4016,"start":777,"end":897}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7L1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7L1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7L1-F1-predicted_aligned_error_v6.png","plddt_mean":86.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLFN11","jax_strain_url":"https://www.jax.org/strain/search?query=SLFN11"},"sequence":{"accession":"Q7Z7L1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z7L1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z7L1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7L1"}},"corpus_meta":[{"pmid":"28196596","id":"PMC_28196596","title":"Chemosensitive 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pathway.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32292519","citation_count":89,"is_preprint":false},{"pmid":"25733708","id":"PMC_25733708","title":"Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25733708","citation_count":89,"is_preprint":false},{"pmid":"25779942","id":"PMC_25779942","title":"SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25779942","citation_count":86,"is_preprint":false},{"pmid":"29391350","id":"PMC_29391350","title":"Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29391350","citation_count":76,"is_preprint":false},{"pmid":"32209474","id":"PMC_32209474","title":"Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32209474","citation_count":66,"is_preprint":false},{"pmid":"33536335","id":"PMC_33536335","title":"SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33536335","citation_count":66,"is_preprint":false},{"pmid":"33339894","id":"PMC_33339894","title":"SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.","date":"2020","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33339894","citation_count":63,"is_preprint":false},{"pmid":"32127465","id":"PMC_32127465","title":"SLFN11 Expression in Advanced Prostate Cancer and Response to Platinum-based Chemotherapy.","date":"2020","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32127465","citation_count":61,"is_preprint":false},{"pmid":"36115853","id":"PMC_36115853","title":"Mechanistic understanding of human SLFN11.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36115853","citation_count":57,"is_preprint":false},{"pmid":"34294893","id":"PMC_34294893","title":"A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers.","date":"2021","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34294893","citation_count":51,"is_preprint":false},{"pmid":"33328609","id":"PMC_33328609","title":"The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response.","date":"2020","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33328609","citation_count":50,"is_preprint":false},{"pmid":"33863777","id":"PMC_33863777","title":"SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33863777","citation_count":45,"is_preprint":false},{"pmid":"32474729","id":"PMC_32474729","title":"Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq.","date":"2020","source":"Virchows Archiv : 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cell cycle arrest in response to DNA-damaging agents (topoisomerase I/II inhibitors, alkylating agents, DNA synthesis inhibitors), as demonstrated by siRNA-mediated silencing in cells with endogenously high and low SLFN11 expression.\",\n      \"method\": \"siRNA knockdown, cell viability assays, cell cycle analysis across NCI-60 panel\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined cellular phenotype replicated across multiple cell lines and cancer types from two independent groups\",\n      \"pmids\": [\"22927417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLFN11 directly interacts with RPA1 and is recruited to sites of DNA damage in an RPA1-dependent manner; SLFN11 inhibits checkpoint maintenance and homologous recombination repair by promoting destabilization of the RPA-ssDNA complex, and the RPA1-binding ability of SLFN11 is required for its function in the DNA damage response.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assays, RPA1-binding mutants, HR repair assays, checkpoint maintenance assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction established, functional mutagenesis confirming RPA1-binding requirement, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26658330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EWS-FLI1 binds near the transcription start site of the SLFN11 promoter and acts as a positive transcriptional regulator of SLFN11 expression in Ewing sarcoma cells; ETS1 also acts as a positive regulator of SLFN11 expression in breast cancer cells.\",\n      \"method\": \"ChIP-seq, promoter-luciferase reporter assays, EWS-FLI1 knockdown and overexpression, ETS1 molecular experiments\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq plus promoter reporter assays plus gain/loss-of-function experiments, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25779942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLFN11 inactivation causes resistance to PARP inhibitors (talazoparib, olaparib) through an irreversible and lethal replication inhibition mechanism independent of ATR-mediated S-phase checkpoint; this resistance is not due to impaired drug penetration or activation of homologous recombination.\",\n      \"method\": \"Isogenic SLFN11-positive and -negative cell lines (CRISPR/shRNA), cell viability assays, xenograft models, genomic analyses\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple isogenic cell line pairs, in vivo validation, mechanistic exclusion of alternative resistance mechanisms\",\n      \"pmids\": [\"27708213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLFN11 epigenetic silencing via promoter CpG island hypermethylation is associated with resistance to platinum compounds; BRCA1-interacting DHX9 RNA helicase (RHA) was identified as a protein partner for SLFN11.\",\n      \"method\": \"DNA methylation microarray (NCI-60), co-immunoprecipitation for DHX9 interaction, in vitro validation of methylation-expression relationship\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP for DHX9 binding, methylation-expression link validated in vitro, single lab\",\n      \"pmids\": [\"26625211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In vivo chemoresistance in small cell lung cancer is associated with marked deposition of H3K27me3 (placed by EZH2) within the SLFN11 gene body, inducing local chromatin condensation and epigenetic silencing of SLFN11.\",\n      \"method\": \"Patient-derived xenograft models of paired chemosensitive/chemoresistant SCLC, ChIP for H3K27me3, EZH2 inhibitor treatment\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo PDX models with ChIP evidence for H3K27me3 deposition at SLFN11 gene body, EZH2 inhibitor reversal, multiple models\",\n      \"pmids\": [\"28196596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In response to replication stress, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3; SLFN11 selectively blocks fork progression while inducing chromatin opening across replication initiation sites; the ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for tight chromatin binding.\",\n      \"method\": \"Chromatin fractionation, co-immunoprecipitation with RPA1/MCM3/CDC45/PCNA, ATPase domain mutants, iPOND (isolation of proteins on nascent DNA), cell death assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including chromatin fractionation, nascent DNA pulldown, domain mutagenesis, replicated with different replication stress agents\",\n      \"pmids\": [\"29395061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLFN11 preferentially inhibits translation of ATR and ATM serine/threonine kinases upon DNA-damaging agent (DDA) treatment based on distinct codon usage; type II tRNAs (including all serine and leucine tRNAs) are cleaved in a SLFN11-dependent manner in response to DDAs; mRNAs with high TTA (Leu) codon usage such as ATR are most susceptible to translational suppression; specific attenuation of tRNA-Leu-TAA suffices to ablate ATR protein expression.\",\n      \"method\": \"Transcriptome analysis, polysome profiling, tRNA cleavage assays, specific tRNA transfection/depletion, immunoblotting for ATR/ATM protein levels\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical tRNA cleavage assays, codon-usage mechanistic link, rescue experiments with specific tRNA, multiple orthogonal methods\",\n      \"pmids\": [\"30374083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Class I (but not class II) HDAC inhibitors (romidepsin, entinostat) strongly induce SLFN11 mRNA and protein expression in cancer cells lacking SLFN11, restoring sensitivity to DNA-damaging agents.\",\n      \"method\": \"HDAC inhibitor treatment panel, immunoblotting, SLFN11 isogenic cell lines, synergy assays with camptothecin\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — class I vs II HDAC inhibitor specificity established, isogenic cell lines used, validated in patient PBMCs, multiple cancer cell lines\",\n      \"pmids\": [\"29391350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLFN11 loss leads to sensitization of tumor cells to IFN-γ-mediated T cell killing; SLFN11 does not influence IFNGR signaling but couples IFNGR signaling to induction of the DNA damage response (DDR) in a context-dependent fashion; loss of SLFN11 reduces IFN-γ-mediated toxicity.\",\n      \"method\": \"Genome-wide haploid genetic screen in HAP1 cells, SLFN11 knockout validation, IFN-γ treatment assays, T cell co-culture killing assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen with functional validation in knockout cells, single lab, IFN-γ coupling mechanism not fully resolved at molecular level\",\n      \"pmids\": [\"30753225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SLFN11 increases chromatin accessibility genome-wide at active promoters in response to replication stress and selectively activates transcription of immediate early genes (IEGs: JUN, FOS, EGR1, NFKB2, ATF3) and cell cycle arrest genes (CDKN1A/p21, GADD45); both chromatin remodeling and IEG activation require the putative ATPase/helicase activity of SLFN11.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), RNA-seq, isogenic SLFN11 KO vs WT cells, ATPase mutants, treatment with CHK1 inhibitor and TOP1 inhibitor\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ATAC-seq and RNA-seq in isogenic cells plus ATPase mutant domain analysis, replicated across NCI-60 cell lines\",\n      \"pmids\": [\"32209474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLFN11 promotes CDT1 degradation by binding to DDB1 of the CUL4-CDT2 E3 ubiquitin ligase complex associated with replication forks, requiring the C-terminus and ATPase domain of SLFN11; this irreversibly arrests replication by degrading CDT1 in response to DNA damage. In SLFN11-KO cells, CDT1 degradation is retarded, enabling replication reactivation. An ATPase mutant (E669K) identified in TCGA contributes to chemoresistance.\",\n      \"method\": \"Genome-wide RNAi screen, Co-IP of SLFN11 with DDB1, CDT1 degradation assays, SLFN11 C-terminus and ATPase domain truncation/mutation analysis, clinical TCGA mutant validation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — unbiased screen plus Co-IP plus domain mutagenesis plus clinical mutant validation, multiple orthogonal methods\",\n      \"pmids\": [\"33536335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLFN11 promotes extensive fork degradation in FANCD2-deficient cells via MRE11 or DNA2 nucleases, dependent on SLFN11 ATPase activity; SLFN11 knockdown in FA cells improves survival upon treatment with interstrand crosslink inducers and reduces chromosome breakage.\",\n      \"method\": \"SLFN11 knockdown in FANCD2-deficient PD20 cells, FANCD2-/-SLFN11-/- HAP1 double knockout, DNA fiber assays for fork degradation, nuclease inhibitors (MRE11, DNA2), RAD51 foci analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — double knockout epistasis, DNA fiber analysis, ATPase domain requirement, nuclease dependency established, orthogonal methods\",\n      \"pmids\": [\"32735670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLFN11 inactivation leads to enhanced global protein ubiquitylation, endoplasmic reticulum stress, unfolded protein response (UPR), and protein aggregation; SLFN11 functions as a regulator of protein quality control and attenuator of ER stress/UPR, and SLFN11-KO cells are sensitized to the UBA1 inhibitor TAK-243.\",\n      \"method\": \"Drug screen (1,978 compounds), proteomic analysis with biotinylated mass spectrometry, RNAi screening, UPR transducer immunoblotting (PERK, p-eIF2α, p-IRE1, ATF6), global ubiquitylation assays in isogenic SLFN11-KO vs WT cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — unbiased screen plus multiple biochemical orthogonal methods plus proteomic analysis plus RNAi screen, single lab\",\n      \"pmids\": [\"33863777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of human SLFN11 determined in dimeric apoenzyme state, bound to tRNA, and in complex with single-stranded DNA; full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state; structural and biochemical studies reveal mechanism of endoribonuclease activity and suggest how SLFN11 may block stressed replication forks.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM), biochemical ATPase assays, tRNA binding assays, ssDNA binding assays, structure-guided mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with biochemical and mutagenesis validation, multiple substrate-bound states resolved\",\n      \"pmids\": [\"36115853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HCMV protein RL1 recruits the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex to degrade SLFN11; SLFN11 potently restricts HCMV infection by inhibiting viral plaque formation and spread.\",\n      \"method\": \"Multiplexed tandem mass tag proteomics screens, identification of RL1-CRL4 complex by proteomics, viral plaque assays, SLFN11 functional restriction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — two orthogonal proteomic screens plus viral plaque assays, mechanism of degradation via CRL4 complex established\",\n      \"pmids\": [\"35105802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLFN11 deficiency in HCC cells promotes macrophage migration and M2-like polarization in a CCL2-dependent manner, which elevates PD-L1 expression in tumor cells via NF-κB pathway activation; mechanistically, SLFN11 suppresses the Notch pathway and CCL2 transcription by binding competitively with TRIM21 to the RRM2 domain of RBM10, thereby inhibiting TRIM21-mediated RBM10 degradation, stabilizing RBM10 and promoting NUMB exon 9 skipping.\",\n      \"method\": \"SLFN11 knockdown in HCC cells, co-culture systems, cytometry by time-of-flight, humanized orthotopic mouse model, Co-IP for SLFN11-RBM10-TRIM21 interactions, splicing analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interactions plus in vivo model plus splicing analysis, single lab, complex mechanism with multiple steps\",\n      \"pmids\": [\"36863689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The RNase domain function of SLFN11 is dispensable for its role in replication stress response (suppressing DNA damage tolerance, destabilizing stalled replication forks, perturbing RAD51 recruitment); the helicase domain is essential for fork degradation, which proceeds via DNA2 and MRE11 nucleases.\",\n      \"method\": \"RNase active-site mutants (critical residues) expressed in SLFN11-/- cells, DNA fiber assays, RAD51 foci analysis, nuclease inhibition (DNA2, MRE11)\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain-specific mutagenesis with functional readouts, distinguishes RNase from helicase domain requirements, multiple assays\",\n      \"pmids\": [\"37469008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLFN11 is recruited to chromatin at unscheduled re-replication sites induced by pevonedistat (neddylation/CRL inhibitor), which causes CDT1 supraphysiologic accumulation; SLFN11 blocks unscheduled re-replication induced by pevonedistat, and SLFN11-proficient cells are selectively killed.\",\n      \"method\": \"High-throughput drug screen (1,978 compounds) in isogenic SLFN11-proficient/-deficient cell pairs, chromatin fractionation, flow cytometry for re-replication, multiple cancer cell databases\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic cell screen plus chromatin recruitment assays plus multiple independent databases, single lab\",\n      \"pmids\": [\"37216280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of SLFN11 bound to tRNA-Leu and tRNA-Met reveal tRNA binding and cleavage mechanisms; phosphorylation at S219 and T230 regulates tRNA recognition and nuclease activity; phosphomimetic S753D mutant adopts a monomeric conformation with ATP binding but loses ssDNA binding and shows reduced ribonuclease activity; S753 phosphorylation site serves as a conformational switch regulating SLFN11 dimerization as well as ATP and ssDNA binding.\",\n      \"method\": \"Cryo-EM structural determination, phosphomimetic mutagenesis (S753D), biochemical assays (ATP binding, ssDNA binding, ribonuclease activity), conformational analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures combined with biochemical and mutagenesis validation, multiple substrate complexes resolved, phosphorylation regulation mechanistically established\",\n      \"pmids\": [\"39627193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLFN11 induces TP53-independent apoptosis through ribosome biogenesis (RiBi) impairment: upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility at rDNA genes; SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis; the Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for ssDNA binding (S753), and RNase sites (E209/E214) are all required.\",\n      \"method\": \"SLFN11-proficient and -deficient isogenic cells, rRNA synthesis assays, RNA Pol I ChIP, ATAC-seq at rDNA, MCL1 protein stability assays, domain mutagenesis (E669, K652, S753, E209/E214), extended across 34 cancer cell lines\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple domain mutants, mechanistic pathway from rRNA inhibition to MCL1 depletion to apoptosis, replicated across 34 cell lines, multiple orthogonal methods\",\n      \"pmids\": [\"39909041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLFN11-mediated tRNA-Leu(TAA) cleavage triggers ER stress and protein aggregate formation leading to cell death regulated by IRE1α; tRNA fragments generated by SLFN11 contribute to ER stress and cell death; SLFN11 regulates proteostasis by cleaving tRNAs, influencing ubiquitin-dependent proteolysis.\",\n      \"method\": \"SLFN11 knockout cells, tRNA-Leu(TAA) transfection rescue, proteomics, IRE1α inhibition, identification of tRNA cleavage sites in cells, ER stress markers\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — rescue by tRNA transfection, IRE1α pathway validation, tRNA cleavage site mapping, proteomic analysis, multiple orthogonal methods\",\n      \"pmids\": [\"40808299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPA exhaustion and single-stranded DNA exposure are the trigger for SLFN11 activation and cell death under heightened replication stress; USP1-WDR48 deubiquitinase complex positively modulates SLFN11 activation; rapid RPA exhaustion upon DNA polymerase α chemical inhibition activates SLFN11-dependent cell death; SLFN11 is the critical determinant of cisplatin sensitivity in PrimPol-deficient cells.\",\n      \"method\": \"CRISPR-based screens, PrimPol-deficient cell models, RPA depletion experiments, USP1-WDR48 co-IP/validation, DNA polymerase α inhibition, epistasis analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screens with epistasis validation, multiple orthogonal mechanistic approaches (RPA depletion, USP1-WDR48, DNA pol α), published in high-quality journal\",\n      \"pmids\": [\"41514018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLFN11 acts upon stalled replication forks to suppress efficient fork restart; in the absence of SLFN11, fork restart proceeds through RFWD3-PRIMPOL-mediated gapped DNA synthesis; SLFN11 antagonizes this pathway by disrupting recruitment of RFWD3 and PRIMPOL to stalled forks, requiring a functional ATPase domain and persistent fork localization but not tRNA hydrolysis or ssDNA binding.\",\n      \"method\": \"Single-molecule DNA fiber analysis, super-resolution microscopy, RFWD3 and PRIMPOL co-IP/recruitment assays, ATPase mutants, tRNA hydrolysis mutants, ssDNA binding mutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — single-molecule DNA fiber and super-resolution microscopy, domain-specific mutants, protein recruitment assays, multiple orthogonal methods\",\n      \"pmids\": [\"41372167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF168 E3 ubiquitin ligase is required for SLFN11 ubiquitylation and chromatin association; ubiquitylation of SLFN11 within its middle linker domain (lysines 390, 391, and 429) with K27-linked polyubiquitin chains is essential for chromatin recruitment; DUB inhibitors drive ubiquitin-dependent SLFN11 chromatin recruitment at promoter regions without detectable DNA damage; both DUB inhibitor- and DNA damage-induced SLFN11 chromatin recruitment are suppressed by TAK-243 (UBA1 inhibitor), demonstrating ubiquitylation dependency.\",\n      \"method\": \"High-throughput imaging screen, Co-IP for ubiquitylation, RNF168 knockout validation, site-specific ubiquitylation mutants (K390/391/429), K27-linkage determination, TAK-243 suppression experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical ubiquitylation mapping with specific lysine mutants, K27-linkage determination, RNF168 KO epistasis, chemical validation with TAK-243, preprint but comprehensive\",\n      \"pmids\": [\"41929013\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SLFN11 physically associates with ribosomal protein RPS4X and blocks the mTOR signaling pathway, thereby inhibiting HCC cell proliferation, migration, and invasion in vitro and impeding HCC growth and metastasis in vivo.\",\n      \"method\": \"Immunoprecipitation, LC-MS/MS, Co-IP, co-immunofluorescence, xenograft mouse models, SLFN11 overexpression/knockdown cell lines\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with mass spectrometry identification of RPS4X, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"32292519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLFN11 specifically binds to the LINE-1 5' untranslated region and blocks RNA polymerase II recruitment, thereby suppressing LINE-1 transcription; SLFN11 promotes heterochromatinization at LINE-1 loci; the inhibitory activity requires the helicase domain.\",\n      \"method\": \"LINE-1 retrotransposition reporter assays, ChIP for SLFN11 binding to LINE-1 5'UTR, RNA Pol II recruitment assays, helicase domain mutants, heterochromatin markers\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin binding assays plus domain mutagenesis plus functional reporter assays, single lab, single paper\",\n      \"pmids\": [\"40497966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLFN11 knockout in GBM cells stimulates expression of NF-κB target genes, consistent with a negative regulatory role on the non-canonical NF-κB pathway; p21 (encoded by CDKN1A) is identified as a direct transcriptional target of NF-κB2 whose expression is stimulated by loss of SLFN11.\",\n      \"method\": \"CRISPR/Cas9 SLFN11 KO, NF-κB target gene expression analysis, orthotopic patient-derived xenograft model, stem cell marker analysis\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with transcriptional profiling and in vivo validation, single lab, NF-κB2-p21 link inferred from transcriptomics\",\n      \"pmids\": [\"36382088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In renal cell carcinoma cells, SLFN11 significantly upregulates CSF2 (encoding GM-CSF) expression; SLFN11-positive RCC cells co-cultured with M0 macrophages secrete higher GM-CSF and promote M1 macrophage polarization; SLFN11 is inversely correlated with BRCA1 expression and promotes proteasomal degradation of BRCA1 protein in ccRCC cells.\",\n      \"method\": \"Transcriptome and proteome analysis of RCC cell lines, macrophage co-culture assays, GM-CSF quantification, multiplex immunofluorescence on patient samples, SLFN11 loss-of-function for BRCA1 levels\",\n      \"journal\": \"Anticancer research / Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — transcriptomic and proteomic identification plus co-culture functional assays plus patient tissue validation, single lab\",\n      \"pmids\": [\"41760260\", \"42260628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLFN11 is an interferon-inducible restriction factor that, upon replication stress, is recruited to stalled replication forks via RPA1-coated ssDNA (triggered by RPA exhaustion) in a manner requiring RNF168-mediated K27-linked polyubiquitylation at lysines 390/391/429; once at forks, its ATPase domain drives chromatin opening, suppresses RFWD3-PRIMPOL-mediated fork restart, promotes CDT1 degradation through the CUL4-DDB1-CDT2 E3 ligase, and causes irreversible replication arrest; in parallel, SLFN11 cleaves type II tRNAs (especially tRNA-Leu-TAA) to selectively suppress translation of ATR/ATM and disrupt proteostasis via ER stress/IRE1α and ribosome biogenesis impairment with MCL1 depletion, collectively inducing p53-independent apoptosis; its expression is epigenetically silenced by EZH2 (H3K27me3) and DNA methylation in ~50% of cancers, and is transcriptionally activated by ETS factors including EWS-FLI1, making it the dominant predictor of sensitivity to DNA-damaging chemotherapies and PARP inhibitors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLFN11 is a replication-stress effector and restriction factor whose expression causally determines cancer cell death in response to DNA-damaging agents and PARP inhibitors, making it the dominant predictor of chemosensitivity [#0, #3]. Upon replication stress, SLFN11 is recruited to stalled forks through direct binding to RPA1 and the MCM3 helicase subunit, and RPA exhaustion with single-stranded DNA exposure serves as the activating trigger, positively modulated by the USP1-WDR48 deubiquitinase complex [#1, #6, #22]; chromatin recruitment requires RNF168-mediated K27-linked polyubiquitylation of SLFN11 at lysines 390/391/429 [#24]. Once at forks, its ATPase/helicase domain drives genome-wide chromatin opening, blocks fork progression, and converts reversible arrest into irreversible replication inhibition [#6, #10]; mechanistically it suppresses RFWD3-PRIMPOL-mediated fork restart [#23], promotes CDT1 degradation by binding DDB1 of the CUL4-CDT2 E3 ligase [#11], and destabilizes the RPA-ssDNA complex to inhibit homologous recombination [#1]. In parallel, SLFN11 functions as an endoribonuclease that cleaves type II tRNAs—especially tRNA-Leu(TAA)—to selectively suppress translation of ATR and ATM based on codon usage and to disrupt proteostasis via IRE1\\u03b1-dependent ER stress [#7, #21], while replication-stress-driven impairment of ribosome biogenesis depletes the short-lived protein MCL1 to induce TP53-independent apoptosis [#20]. SLFN11 expression is epigenetically silenced through EZH2-mediated H3K27me3 deposition and promoter CpG hypermethylation in chemoresistant tumors, and is transcriptionally activated by ETS factors including EWS-FLI1 [#2, #4, #5]; class I HDAC inhibitors and EZH2 inhibitors can restore its expression and re-sensitize cells to DNA-damaging therapy [#5, #8]. Cryo-EM structures resolve SLFN11 as a dimer bound to tRNA and ssDNA in which full-length protein adopts an autoinhibited helicase state, with phosphorylation at S753 acting as a conformational switch governing dimerization, ATP and ssDNA binding [#14, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that SLFN11 is not a bystander biomarker but a causal determinant of whether cancer cells die in response to DNA-damaging agents, defining the central functional question for the gene.\",\n      \"evidence\": \"siRNA knockdown with viability and cell cycle readouts across the NCI-60 panel\",\n      \"pmids\": [\"22927417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular mechanism linking SLFN11 to death\", \"No protein partners or biochemical activity identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the physical route by which SLFN11 senses DNA damage—direct RPA1 binding and RPA1-dependent recruitment—and showed it acts by destabilizing RPA-ssDNA to block HR and checkpoint maintenance.\",\n      \"evidence\": \"Co-IP, RPA1-binding mutants, HR and checkpoint assays\",\n      \"pmids\": [\"26658330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic activity at forks not yet defined\", \"Did not address how RPA-bound SLFN11 enforces irreversibility\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected SLFN11 expression to transcriptional control by oncogenic ETS factors, explaining why expression varies across tumor types.\",\n      \"evidence\": \"ChIP-seq, promoter reporter, EWS-FLI1 and ETS1 gain/loss-of-function\",\n      \"pmids\": [\"25779942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address epigenetic silencing mechanisms\", \"Scope limited to Ewing sarcoma and breast cancer contexts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that SLFN11 loss—whether by inactivation or promoter hypermethylation—drives resistance to PARP inhibitors and platinum, establishing the clinical resistance axis and a candidate partner DHX9.\",\n      \"evidence\": \"Isogenic CRISPR/shRNA lines, xenografts, methylation microarray, DHX9 Co-IP\",\n      \"pmids\": [\"27708213\", \"26625211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DHX9 interaction rests on single Co-IP without functional validation\", \"Mechanism of irreversible replication inhibition not yet resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a chromatin-based silencing mechanism (EZH2/H3K27me3 over the gene body) driving in vivo chemoresistance and showed it is pharmacologically reversible.\",\n      \"evidence\": \"Chemosensitive/resistant SCLC PDX models, H3K27me3 ChIP, EZH2 inhibitor reversal\",\n      \"pmids\": [\"28196596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address relative contribution of methylation vs H3K27me3 across tumor types\", \"Upstream signals recruiting EZH2 to SLFN11 unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the core fork-acting mechanism: SLFN11 binds stressed forks via RPA1/MCM3 and uses its ATPase domain to open chromatin and block forks, separating tight binding from catalytic execution.\",\n      \"evidence\": \"Chromatin fractionation, iPOND, Co-IP with RPA1/MCM3/CDC45/PCNA, ATPase mutants\",\n      \"pmids\": [\"29395061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate of the ATPase activity not defined\", \"Did not show how chromatin opening enforces irreversibility\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a parallel translational arm—SLFN11-dependent type II tRNA cleavage selectively suppressing ATR/ATM via codon usage—revealing endoribonuclease activity as a distinct effector mechanism.\",\n      \"evidence\": \"Polysome profiling, tRNA cleavage assays, codon-usage analysis, specific tRNA depletion/rescue\",\n      \"pmids\": [\"30374083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between RNase and fork activities not yet dissected\", \"Structural basis of tRNA selectivity unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that class I HDAC inhibitors can re-induce SLFN11 in silenced cells, providing a second pharmacological strategy to restore chemosensitivity.\",\n      \"evidence\": \"HDAC inhibitor panel, isogenic cell lines, immunoblot, camptothecin synergy, patient PBMCs\",\n      \"pmids\": [\"29391350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin mechanism of induction not mapped\", \"Did not test combination durability in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked SLFN11 to immune-mediated killing by coupling IFN-\\u03b3 signaling to the DNA damage response, broadening its role beyond chemotherapy.\",\n      \"evidence\": \"Genome-wide haploid screen in HAP1, knockout validation, T cell co-culture killing\",\n      \"pmids\": [\"30753225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular coupling of IFNGR signaling to DDR not resolved\", \"Single lab, context-dependent effect\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that SLFN11's ATPase-dependent chromatin remodeling extends to transcription, selectively activating immediate early and cell cycle arrest genes including CDKN1A and GADD45.\",\n      \"evidence\": \"ATAC-seq, RNA-seq in isogenic cells, ATPase mutants, CHK1/TOP1 inhibitor treatment\",\n      \"pmids\": [\"32209474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether transcriptional activation contributes to cell death vs is a byproduct unclear\", \"Direct chromatin targets of remodeling not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported an additional partner RPS4X and an mTOR-suppressive, growth-inhibitory role in HCC, extending SLFN11 function to translation/proliferation control.\",\n      \"evidence\": \"IP-LC-MS/MS, Co-IP, co-IF, xenografts, overexpression/knockdown\",\n      \"pmids\": [\"32292519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RPS4X interaction not reciprocally validated against fork/RNase functions\", \"Single lab, single tumor context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified CDT1 degradation via SLFN11 binding to DDB1 of the CUL4-CDT2 ligase as a concrete mechanism enforcing irreversible replication arrest, with a clinical ATPase mutant validating relevance.\",\n      \"evidence\": \"Genome-wide RNAi screen, SLFN11-DDB1 Co-IP, CDT1 degradation assays, domain mutants, TCGA E669K mutant\",\n      \"pmids\": [\"33536335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDT1 loss couples to apoptosis not detailed\", \"Relationship to chromatin opening mechanism unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established context-dependent fork degradation: in FANCD2-deficient cells SLFN11 drives MRE11/DNA2-mediated fork resection, defining a deleterious-genome-instability arm.\",\n      \"evidence\": \"Knockdown in PD20, FANCD2/SLFN11 double KO, DNA fiber assays, nuclease inhibitors, RAD51 foci\",\n      \"pmids\": [\"32735670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway operates in FA-proficient cells unclear\", \"ATPase substrate driving resection not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a proteostasis function—SLFN11 attenuates ER stress/UPR and global ubiquitylation, sensitizing its loss to UBA1 inhibition.\",\n      \"evidence\": \"1,978-compound screen, biotin proteomics, RNAi, UPR transducer immunoblots, ubiquitylation assays\",\n      \"pmids\": [\"33863777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between SLFN11 and UPR transducers not fully defined at the time\", \"Did not connect to tRNA cleavage directly\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the first structural framework: cryo-EM of dimeric SLFN11 bound to tRNA and ssDNA, showing the helicase domain is autoinhibited and full-length protein does not hydrolyze ATP.\",\n      \"evidence\": \"Cryo-EM, ATPase/tRNA/ssDNA binding assays, structure-guided mutagenesis\",\n      \"pmids\": [\"36115853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How autoinhibition is relieved in cells not resolved\", \"Active conformation at forks not captured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SLFN11 restricts HCMV and is targeted for degradation by viral RL1 via CRL4, establishing an antiviral restriction-factor role.\",\n      \"evidence\": \"Tandem mass tag proteomics, RL1-CRL4 identification, viral plaque assays\",\n      \"pmids\": [\"35105802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SLFN11 restricts viral replication not defined\", \"Whether antiviral and fork functions share machinery unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported SLFN11 as a negative regulator of non-canonical NF-\\u03baB signaling, with NF-\\u03baB2-driven p21 induction upon loss, linking SLFN11 to transcriptional/immune programs in GBM.\",\n      \"evidence\": \"CRISPR KO, NF-\\u03baB target profiling, orthotopic PDX\",\n      \"pmids\": [\"36382088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-\\u03baB2-p21 link inferred from transcriptomics, not direct\", \"Single lab, mechanism of NF-\\u03baB suppression unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissected domain division of labor, showing the RNase domain is dispensable for the replication-stress response while the helicase domain is essential for fork degradation via DNA2/MRE11.\",\n      \"evidence\": \"RNase active-site mutants in SLFN11-/- cells, DNA fiber assays, RAD51 foci, nuclease inhibition\",\n      \"pmids\": [\"37469008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile with cryo-EM finding of autoinhibited ATPase\", \"Substrate of helicase domain still undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the irreversible-arrest model to re-replication stress, showing SLFN11 is recruited to pevonedistat-induced re-replication sites and selectively kills proficient cells.\",\n      \"evidence\": \"1,978-compound isogenic screen, chromatin fractionation, flow cytometry, cancer databases\",\n      \"pmids\": [\"37216280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of re-replication block not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Described an immune-modulatory mechanism in HCC: SLFN11 stabilizes RBM10 by competing with TRIM21, altering NUMB splicing and suppressing CCL2/Notch to limit M2 polarization and PD-L1.\",\n      \"evidence\": \"Knockdown, co-culture, CyTOF, humanized orthotopic model, Co-IP, splicing analysis\",\n      \"pmids\": [\"36863689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multi-step mechanism from a single lab\", \"Relationship of RBM10 binding to replication functions unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved tRNA recognition/cleavage structurally and identified S753 phosphorylation as a conformational switch controlling dimerization, ATP and ssDNA binding, plus S219/T230 phosphoregulation of nuclease activity.\",\n      \"evidence\": \"Cryo-EM with tRNA-Leu/Met, phosphomimetic S753D, ATP/ssDNA/RNase assays\",\n      \"pmids\": [\"39627193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases/phosphatases controlling these sites not identified\", \"How phospho-switch is timed during replication stress unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated the death mechanism: replication-stress-driven ribosome biogenesis impairment depletes short-lived MCL1, producing TP53-independent apoptosis, with multiple domains required.\",\n      \"evidence\": \"Isogenic cells, rRNA synthesis assays, RNA Pol I ChIP, rDNA ATAC-seq, MCL1 stability, domain mutants across 34 lines\",\n      \"pmids\": [\"39909041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fork engagement triggers rRNA shutdown not fully mapped\", \"Relative contribution of RiBi vs CDT1/tRNA arms to death unquantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected the tRNA-cleavage arm to proteostasis collapse, showing tRNA-Leu(TAA) fragments drive IRE1\\u03b1-dependent ER stress and aggregate-associated death.\",\n      \"evidence\": \"Knockout cells, tRNA-Leu(TAA) rescue, proteomics, IRE1\\u03b1 inhibition, cleavage-site mapping\",\n      \"pmids\": [\"40808299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How tRNA fragments are sensed by IRE1\\u03b1 not defined\", \"Crosstalk with the fork/RiBi arms unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the activating trigger—RPA exhaustion and ssDNA exposure—and a positive regulator USP1-WDR48, and showed SLFN11 antagonizes RFWD3-PRIMPOL-mediated fork restart through ATPase activity and persistent localization rather than tRNA hydrolysis or ssDNA binding.\",\n      \"evidence\": \"CRISPR screens, PrimPol-deficient models, RPA depletion, USP1-WDR48 validation, DNA pol \\u03b1 inhibition; DNA fiber and super-resolution with domain mutants\",\n      \"pmids\": [\"41514018\", \"41372167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP1-WDR48 modulates SLFN11 mechanistically unclear\", \"Reconciliation of ssDNA-independent fork function with RPA-dependent recruitment incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the ubiquitin signal for chromatin recruitment: RNF168-dependent K27-linked polyubiquitylation at K390/391/429 is required, and recruitment is UBA1-dependent and inducible by DUB inhibitors even without DNA damage.\",\n      \"evidence\": \"High-throughput imaging screen, ubiquitylation Co-IP, RNF168 KO, site-specific lysine mutants, K27-linkage mapping, TAK-243 suppression (preprint)\",\n      \"pmids\": [\"41929013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"How K27 chains are read for chromatin engagement unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended SLFN11's immune-microenvironment role to RCC, where it upregulates CSF2/GM-CSF promoting M1 polarization and promotes proteasomal BRCA1 degradation.\",\n      \"evidence\": \"Transcriptome/proteome, macrophage co-culture, GM-CSF quantification, multiplex IF, loss-of-function for BRCA1\",\n      \"pmids\": [\"41760260\", \"42260628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BRCA1 degradation mechanism not biochemically defined\", \"Single tumor context, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLFN11's distinct effector arms—ATPase-driven fork block/CDT1 degradation, tRNA cleavage, ribosome biogenesis shutdown, and chromatin/transcriptional remodeling—are coordinated in time and which dominates the death decision in a given context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model quantifying relative contributions of each arm\", \"Cell-type determinants selecting one effector pathway over another unknown\", \"Active in-cell conformation relative to the autoinhibited apo structure not captured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [7, 14, 19, 21]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 14, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 19, 26]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [6, 10, 11, 17, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [7, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 10, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 6, 12, 17]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6, 11, 18, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 20, 21]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 20, 21]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [13, 21, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 10, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RPA1\", \"MCM3\", \"DDB1\", \"DHX9\", \"RPS4X\", \"RBM10\", \"USP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}