Affinage

SLFN11

Schlafen family member 11 · UniProt Q7Z7L1

Length
901 aa
Mass
102.8 kDa
Annotated
2026-06-10
88 papers in source corpus 30 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2012 High

    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

    PMID:22927417

    Open questions at the time
    • Did not define the molecular mechanism linking SLFN11 to death
    • No protein partners or biochemical activity identified
  2. 2015 High

    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

    PMID:26658330

    Open questions at the time
    • Catalytic activity at forks not yet defined
    • Did not address how RPA-bound SLFN11 enforces irreversibility
  3. 2015 High

    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

    PMID:25779942

    Open questions at the time
    • Did not address epigenetic silencing mechanisms
    • Scope limited to Ewing sarcoma and breast cancer contexts
  4. 2016 High

    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

    PMID:26625211 PMID:27708213

    Open questions at the time
    • DHX9 interaction rests on single Co-IP without functional validation
    • Mechanism of irreversible replication inhibition not yet resolved
  5. 2017 High

    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

    PMID:28196596

    Open questions at the time
    • Did not address relative contribution of methylation vs H3K27me3 across tumor types
    • Upstream signals recruiting EZH2 to SLFN11 unclear
  6. 2018 High

    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

    PMID:29395061

    Open questions at the time
    • Substrate of the ATPase activity not defined
    • Did not show how chromatin opening enforces irreversibility
  7. 2018 High

    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

    PMID:30374083

    Open questions at the time
    • Relationship between RNase and fork activities not yet dissected
    • Structural basis of tRNA selectivity unknown
  8. 2018 High

    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

    PMID:29391350

    Open questions at the time
    • Direct chromatin mechanism of induction not mapped
    • Did not test combination durability in vivo
  9. 2019 Medium

    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

    PMID:30753225

    Open questions at the time
    • Molecular coupling of IFNGR signaling to DDR not resolved
    • Single lab, context-dependent effect
  10. 2020 High

    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

    PMID:32209474

    Open questions at the time
    • Whether transcriptional activation contributes to cell death vs is a byproduct unclear
    • Direct chromatin targets of remodeling not enumerated
  11. 2020 Medium

    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

    PMID:32292519

    Open questions at the time
    • RPS4X interaction not reciprocally validated against fork/RNase functions
    • Single lab, single tumor context
  12. 2021 High

    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

    PMID:33536335

    Open questions at the time
    • How CDT1 loss couples to apoptosis not detailed
    • Relationship to chromatin opening mechanism unresolved
  13. 2021 High

    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

    PMID:32735670

    Open questions at the time
    • Whether this pathway operates in FA-proficient cells unclear
    • ATPase substrate driving resection not identified
  14. 2021 High

    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

    PMID:33863777

    Open questions at the time
    • Mechanistic link between SLFN11 and UPR transducers not fully defined at the time
    • Did not connect to tRNA cleavage directly
  15. 2022 High

    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

    PMID:36115853

    Open questions at the time
    • How autoinhibition is relieved in cells not resolved
    • Active conformation at forks not captured
  16. 2022 High

    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

    PMID:35105802

    Open questions at the time
    • Mechanism by which SLFN11 restricts viral replication not defined
    • Whether antiviral and fork functions share machinery unknown
  17. 2022 Medium

    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

    PMID:36382088

    Open questions at the time
    • NF-κB2-p21 link inferred from transcriptomics, not direct
    • Single lab, mechanism of NF-κB suppression unclear
  18. 2023 High

    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

    PMID:37469008

    Open questions at the time
    • Did not reconcile with cryo-EM finding of autoinhibited ATPase
    • Substrate of helicase domain still undefined
  19. 2023 Medium

    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

    PMID:37216280

    Open questions at the time
    • Mechanism of re-replication block not detailed
    • Single lab
  20. 2023 Medium

    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

    PMID:36863689

    Open questions at the time
    • Multi-step mechanism from a single lab
    • Relationship of RBM10 binding to replication functions unclear
  21. 2024 High

    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

    PMID:39627193

    Open questions at the time
    • Kinases/phosphatases controlling these sites not identified
    • How phospho-switch is timed during replication stress unknown
  22. 2025 High

    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

    PMID:39909041

    Open questions at the time
    • How fork engagement triggers rRNA shutdown not fully mapped
    • Relative contribution of RiBi vs CDT1/tRNA arms to death unquantified
  23. 2025 High

    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

    PMID:40808299

    Open questions at the time
    • How tRNA fragments are sensed by IRE1α not defined
    • Crosstalk with the fork/RiBi arms unresolved
  24. 2025 High

    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

    PMID:41372167 PMID:41514018

    Open questions at the time
    • How USP1-WDR48 modulates SLFN11 mechanistically unclear
    • Reconciliation of ssDNA-independent fork function with RPA-dependent recruitment incomplete
  25. 2026 High

    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)

    PMID:41929013

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • How K27 chains are read for chromatin engagement unknown
  26. 2026 Medium

    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

    PMID:41760260 PMID:42260628

    Open questions at the time
    • BRCA1 degradation mechanism not biochemically defined
    • Single tumor context, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 5 GO:0140098 catalytic activity, acting on RNA 4 GO:0003677 DNA binding 3 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005694 chromosome 3 GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 4 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
DDB1DHX9MCM3RBM10RPA1RPS4XUSP1

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 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. siRNA knockdown, cell viability assays, cell cycle analysis across NCI-60 panel Proceedings of the National Academy of Sciences of the United States of America High 22927417
2015 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. Co-immunoprecipitation, direct interaction assays, RPA1-binding mutants, HR repair assays, checkpoint maintenance assays EMBO reports High 26658330
2015 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. ChIP-seq, promoter-luciferase reporter assays, EWS-FLI1 knockdown and overexpression, ETS1 molecular experiments Clinical cancer research High 25779942
2016 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. Isogenic SLFN11-positive and -negative cell lines (CRISPR/shRNA), cell viability assays, xenograft models, genomic analyses Oncotarget High 27708213
2016 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. DNA methylation microarray (NCI-60), co-immunoprecipitation for DHX9 interaction, in vitro validation of methylation-expression relationship Oncotarget Medium 26625211
2017 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. Patient-derived xenograft models of paired chemosensitive/chemoresistant SCLC, ChIP for H3K27me3, EZH2 inhibitor treatment Cancer cell High 28196596
2018 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. Chromatin fractionation, co-immunoprecipitation with RPA1/MCM3/CDC45/PCNA, ATPase domain mutants, iPOND (isolation of proteins on nascent DNA), cell death assays Molecular cell High 29395061
2018 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. Transcriptome analysis, polysome profiling, tRNA cleavage assays, specific tRNA transfection/depletion, immunoblotting for ATR/ATM protein levels Nature structural & molecular biology High 30374083
2018 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. HDAC inhibitor treatment panel, immunoblotting, SLFN11 isogenic cell lines, synergy assays with camptothecin Clinical cancer research High 29391350
2019 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. Genome-wide haploid genetic screen in HAP1 cells, SLFN11 knockout validation, IFN-γ treatment assays, T cell co-culture killing assays PloS one Medium 30753225
2020 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. ATAC-seq (chromatin accessibility), RNA-seq, isogenic SLFN11 KO vs WT cells, ATPase mutants, treatment with CHK1 inhibitor and TOP1 inhibitor Cell reports High 32209474
2021 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 33536335
2021 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. 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 Blood High 32735670
2021 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. 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 Cancer research High 33863777
2022 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. Cryo-electron microscopy (cryo-EM), biochemical ATPase assays, tRNA binding assays, ssDNA binding assays, structure-guided mutagenesis Nature communications High 36115853
2022 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. Multiplexed tandem mass tag proteomics screens, identification of RL1-CRL4 complex by proteomics, viral plaque assays, SLFN11 functional restriction assays Proceedings of the National Academy of Sciences of the United States of America High 35105802
2023 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. 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 Gastroenterology Medium 36863689
2023 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. RNase active-site mutants (critical residues) expressed in SLFN11-/- cells, DNA fiber assays, RAD51 foci analysis, nuclease inhibition (DNA2, MRE11) Genes to cells High 37469008
2023 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. 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 Molecular cancer therapeutics Medium 37216280
2024 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. Cryo-EM structural determination, phosphomimetic mutagenesis (S753D), biochemical assays (ATP binding, ssDNA binding, ribonuclease activity), conformational analysis Nature communications High 39627193
2025 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. 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 Molecular cell High 39909041
2025 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. SLFN11 knockout cells, tRNA-Leu(TAA) transfection rescue, proteomics, IRE1α inhibition, identification of tRNA cleavage sites in cells, ER stress markers Nucleic acids research High 40808299
2025 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. CRISPR-based screens, PrimPol-deficient cell models, RPA depletion experiments, USP1-WDR48 co-IP/validation, DNA polymerase α inhibition, epistasis analysis Nature cell biology High 41514018
2025 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. Single-molecule DNA fiber analysis, super-resolution microscopy, RFWD3 and PRIMPOL co-IP/recruitment assays, ATPase mutants, tRNA hydrolysis mutants, ssDNA binding mutants Nature communications High 41372167
2026 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. 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 bioRxivpreprint High 41929013
2020 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. Immunoprecipitation, LC-MS/MS, Co-IP, co-immunofluorescence, xenograft mouse models, SLFN11 overexpression/knockdown cell lines Theranostics Medium 32292519
2025 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. LINE-1 retrotransposition reporter assays, ChIP for SLFN11 binding to LINE-1 5'UTR, RNA Pol II recruitment assays, helicase domain mutants, heterochromatin markers Cells Medium 40497966
2022 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. CRISPR/Cas9 SLFN11 KO, NF-κB target gene expression analysis, orthotopic patient-derived xenograft model, stem cell marker analysis Cancer research communications Medium 36382088
2026 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. 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 Anticancer research / Journal of experimental & clinical cancer research Medium 41760260 42260628

Source papers

Stage 0 corpus · 88 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis. Cancer cell 420 28196596
2016 PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 302 27440269
2012 Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proceedings of the National Academy of Sciences of the United States of America 291 22927417
2016 Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 251 27708213
2018 SLFN11 Blocks Stressed Replication Forks Independently of ATR. Molecular cell 221 29395061
2017 Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer. Oncotarget 194 28212573
2016 Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs. Oncotarget 146 26625211
2019 Schlafen 11 (SLFN11), a restriction factor for replicative stress induced by DNA-targeting anti-cancer therapies. Pharmacology & therapeutics 138 31128155
2015 SLFN11 inhibits checkpoint maintenance and homologous recombination repair. EMBO reports 132 26658330
2020 BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Science translational medicine 121 32075943
2018 DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs. Nature structural & molecular biology 118 30374083
2023 Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular Carcinoma. Gastroenterology 107 36863689
2020 SLFN11 inhibits hepatocellular carcinoma tumorigenesis and metastasis by targeting RPS4X via mTOR pathway. Theranostics 89 32292519
2015 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. Clinical cancer research : an official journal of the American Association for Cancer Research 89 25733708
2015 SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 86 25779942
2018 Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 76 29391350
2021 SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors. Proceedings of the National Academy of Sciences of the United States of America 66 33536335
2020 Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress. Cell reports 66 32209474
2020 SLFN11 informs on standard of care and novel treatments in a wide range of cancer models. British journal of cancer 63 33339894
2020 SLFN11 Expression in Advanced Prostate Cancer and Response to Platinum-based Chemotherapy. Molecular cancer therapeutics 61 32127465
2022 Mechanistic understanding of human SLFN11. Nature communications 57 36115853
2021 A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers. British journal of cancer 51 34294893
2020 The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response. British journal of cancer 50 33328609
2021 SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243. Cancer research 45 33863777
2020 Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq. Virchows Archiv : an international journal of pathology 45 32474729
2021 Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response. British journal of cancer 44 34663950
2019 SLFN11 can sensitize tumor cells towards IFN-γ-mediated T cell killing. PloS one 43 30753225
2019 Radiosensitization of head and neck squamous cell carcinoma lines by DNA-PK inhibitors is more effective than PARP-1 inhibition and is enhanced by SLFN11 and hypoxia. International journal of radiation biology 39 31490091
2024 Phase II Randomized Study of Maintenance Atezolizumab Versus Atezolizumab Plus Talazoparib in Patients With SLFN11 Positive Extensive-Stage SCLC: S1929. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 38 39505259
2015 High SLFN11 expression predicts better survival for patients with KRAS exon 2 wild type colorectal cancer after treated with adjuvant oxaliplatin-based treatment. BMC cancer 37 26525741
2017 Report on the first SLFN11 monothematic workshop: from function to role as a biomarker in cancer. Journal of translational medicine 35 28969705
2021 SLFN11 promotes stalled fork degradation that underlies the phenotype in Fanconi anemia cells. Blood 33 32735670
2021 SLFN11 biomarker status predicts response to lurbinectedin as a single agent and in combination with ATR inhibition in small cell lung cancer. Translational lung cancer research 33 35004241
2021 SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer. JCI insight 31 34549724
2022 Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. Proceedings of the National Academy of Sciences of the United States of America 29 35105802
2021 Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR. Molecular cancer therapeutics 27 33653945
2022 Dynamic expression of Schlafen 11 (SLFN11) in circulating tumour cells as a liquid biomarker in small cell lung cancer. British journal of cancer 26 35440668
2021 Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development. PloS one 26 33513156
2023 Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan. NPJ breast cancer 25 37567892
2025 SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis. Molecular cell 22 39909041
2021 FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11. Acta pharmacologica Sinica 20 34893686
2019 SLFN11 is a general target for enhancing the sensitivity of cancer to chemotherapy (DNA-damaging agents). Journal of drug targeting 20 31092045
2019 Methylation of SLFN11 promotes gastric cancer growth and increases gastric cancer cell resistance to cisplatin. Journal of Cancer 19 31762822
2024 The emerging role of Schlafen-11 (SLFN11) in predicting response to anticancer treatments: Focus on small cell lung cancer. Cancer treatment reviews 18 38797062
2024 SLFN11 is a BRCA Independent Biomarker for the Response to Platinum-Based Chemotherapy in High-Grade Serous Ovarian Cancer and Clear Cell Ovarian Carcinoma. Molecular cancer therapeutics 17 37717249
2021 SLFN11 is Widely Expressed in Pediatric Sarcoma and Induces Variable Sensitization to Replicative Stress Caused By DNA-Damaging Agents. Molecular cancer therapeutics 16 34413129
2024 Phosphorylation-mediated conformational change regulates human SLFN11. Nature communications 12 39627193
2023 Modulation of SLFN11 induces changes in DNA Damage response in breast cancer. Cancer cell international 12 38001424
2024 Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets: A Study of 127 Entities Represented by 6658 Tumors. The American journal of surgical pathology 11 39185596
2023 Mouse Slfn8 and Slfn9 genes complement human cells lacking SLFN11 during the replication stress response. Communications biology 11 37833372
2023 Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication. Molecular cancer therapeutics 10 37216280
2022 SLFN11 negatively regulates non-canonical NFkB signaling to promote glioblastoma progression. Cancer research communications 10 36382088
2021 Study of Clinical Predictive Value and Immune Characterization of SLFN11 in Clear Cell Renal Cell Carcinoma. International journal of general medicine 10 34675634
2025 SLFN11: a pan-cancer biomarker for DNA-targeted drugs sensitivity and therapeutic strategy guidance. Frontiers in oncology 9 40766331
2024 Correlation of Systemic Inflammation Parameters and Serum SLFN11 in Small Cell Lung Cancer-A Prospective Pilot Study. Biomedicines 9 38790938
2023 The ribonuclease domain function is dispensable for SLFN11 to mediate cell fate decision during replication stress response. Genes to cells : devoted to molecular & cellular mechanisms 8 37469008
2024 SLFN11 promotes clear cell renal cell carcinoma progression via the PI3K/AKT signaling pathway. Medical oncology (Northwood, London, England) 6 38206539
2024 The role of SLFN11 in DNA replication stress response and its implications for the Fanconi anemia pathway. DNA repair 6 39096698
2024 SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells. Biochimica et biophysica acta. Molecular basis of disease 6 39117290
2025 SLFN11-mediated tRNA regulation induces cell death by disrupting proteostasis in response to DNA-damaging agents. Nucleic acids research 5 40808299
2025 Synergistic Effects of ATR Inhibition and Lurbinectedin in Soft-Tissue Sarcomas: The Predictive Role of SLFN11 Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 3 40560936
2024 Electrochemical immunosensor for the predictive cancer biomarker SLFN11 using reduced graphene oxide/MIL-101(Cr)-NH2 composite. International journal of biological macromolecules 3 39626816
2025 Lost in translation: SLFN11 induces p53-independent apoptosis. Molecular cell 2 40118034
2025 SLFN11 Restricts LINE-1 Mobility. Cells 2 40497966
2025 From predictive biomarker to therapeutic target: the dual role of SLFN11 in chemotherapy sensitivity. Cancer chemotherapy and pharmacology 2 40531330
2025 SLFN11, far from being limited to responding to cancer DNA damage. Clinical and experimental medicine 2 40856812
2024 Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML. Blood neoplasia 2 40552140
2026 RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress. Nature cell biology 1 41514018
2025 SLFN11-mediated tRNA regulation induces cell death by disrupting proteostasis in response to DNA-damaging agents. bioRxiv : the preprint server for biology 1 39829761
2025 MMR deficiency is frequent in colorectal carcinomas with diffuse SLFN11 immunostaining: clinicopathologic and molecular study of 31 cases identified among 3,300 tumors. The journal of pathology. Clinical research 1 40105034
2025 Lack of association between SLFN11 expression and treatment efficacy or survival outcomes in patients with pancreatic ductal adenocarcinoma. Journal of cancer research and clinical oncology 1 40346357
2025 MET and SLFN11 as a Players in the SCLC Molecular Subtyping Game. International journal of molecular sciences 1 40649874
2025 Clinical insight on the pathway of SLFN11 as emergent biomarker in SCLC. Critical reviews in oncology/hematology 1 40819743
2025 Co-expression of CD30 and SLFN11 serves as a dual biomarker for the treatment of cutaneous T-cell lymphoma. NAR cancer 1 41064808
2025 SLFN11 counteracts the RFWD3-PRIMPOL DNA damage tolerance axis to restrain gapped DNA synthesis in response to replication stress. Nature communications 1 41372167
2018 SLFN11 Blocks DNA Replication Independently of ATR Activity. Cancer discovery 1 29439152
2026 Targeting glycerophospholipid biosynthesis overcomes chemoresistance driven by SLFN11 loss in Ewing sarcoma. Cell death & disease 0 41620417
2026 Correction: SLFN11: a pan-cancer biomarker for DNA-targeted drugs sensitivity and therapeutic strategy guidance. Frontiers in oncology 0 41717411
2026 SLFN11 Drives GM-CSF-mediated M1 Macrophage Polarization and Enhances Immunotherapy Response in Renal Cell Carcinoma. Anticancer research 0 41760260
2026 Schlafen 11 (SLFN11) And Tumor-Infiltrating Lymphocytes (TILs): Dual Predictive Biomarkers In Ovarian Serous Carcinoma. Asian Pacific journal of cancer prevention : APJCP 0 41793692
2026 SLFN11 Enhances PARPi Sensitivity in Ovarian Cancer via Ubiquitin-Mediated Stabilization. DNA and cell biology 0 41830441
2026 Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase (DUB) and RNF168. bioRxiv : the preprint server for biology 0 41929013
2026 Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase (DUB) and RNF168. Research square 0 41994138
2026 Schlafen 11 (SLFN11) overexpression and nucleolar localization in response to bortezomib in multiple myeloma. bioRxiv : the preprint server for biology 0 42051302
2026 Alkylating agents activate an SLFN11-dependent vulnerability that confers PARP-1 inhibitor sensitivity in kidney cancer. Journal of experimental & clinical cancer research : CR 0 42260628
2025 SLFN11 puts the brakes on Alternative lengthening of telomeres. bioRxiv : the preprint server for biology 0 41427320
2024 [SLFN11 inhibition rescues the Fanconi anemia phenotype by stabilizing stalled replication forks]. [Rinsho ketsueki] The Japanese journal of clinical hematology 0 39935221
2015 SLFN11: Achilles' Heel or Troublemaker. Clinical cancer research : an official journal of the American Association for Cancer Research 0 26034126

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