Affinage

SLX4

Structure-specific endonuclease subunit SLX4 · UniProt Q8IY92

Length
1834 aa
Mass
200.0 kDa
Annotated
2026-06-10
100 papers in source corpus 57 papers cited in narrative 57 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLX4 (BTBD12/FANCP) is a multidomain scaffold that assembles and activates a modular toolkit of structure-specific endonucleases—XPF-ERCC1, MUS81-EME1, and SLX1—to process branched DNA intermediates arising during replication, recombination, and interstrand crosslink (ICL) repair (PMID:19596235, PMID:19595721). Through direct contacts it stimulates each partner nuclease and directs substrate specificity: the SLX1-SLX4 module is a Holliday junction resolvase and 5'-flap endonuclease (PMID:19596236, PMID:12832395), the N-terminal SLX4-XPF-ERCC1 interaction enhances XPF-ERCC1 activity up to 100-fold and executes the unhooking incisions of replication-coupled ICL repair (PMID:24726326, PMID:24726325), and CDK1-driven phosphorylation of the MUS81-binding region folds an SAP domain that recruits MUS81-EME1 into a stable SLX-MUS holoenzyme providing efficient HJ resolution at G2/M (PMID:24076221, PMID:36288699). Structural work shows SLX4 activates SLX1 by displacing its autoinhibitory homodimer and that the SLX4 SAP domain positions 5'-flap substrates for accurate cleavage (PMID:25753413, PMID:34181713). SLX4 itself dimerizes via its BTB domain, an event required for foci formation and telomeric localization (PMID:27131364). Damage-site recruitment is multi-modal: the UBZ1 domain reads K63-linked polyubiquitin deposited by RNF168 and ubiquitylated FANCD2 at ICLs (PMID:24794496, PMID:21464321, PMID:34706224), while SUMO-interacting motifs (cooperating with PARylation) target SLX4 to resected/laser damage, fragile sites, PML bodies, and ALT telomeres (PMID:25533185, PMID:25722289). At telomeres SLX4 docks on the shelterin subunit TRF2 via an HxLxP motif to deliver its nucleases and regulate telomere length and fragility (PMID:24012755, PMID:23994477), and it drives recombination-based ALT telomere processing in opposition to the BLM-TOP3A-RMI dissolution pathway (PMID:28877996). SLX4 additionally functions as a SUMO E3 ligase that SUMOylates itself and XPF (PMID:25533188), forms SUMO/dimerization-driven nuclear condensates that compartmentalize the SUMO-RNF4 pathway and promote topoisomerase-1 DPC extraction (PMID:37059091), interacts with the helicase RTEL1 to prevent replication-transcription conflicts (PMID:32398829), and binds MSH2 through a SHIP box to suppress MutSα-dependent mismatch repair (PMID:35166826). SLX4 protein levels are buffered by RNF4-mediated ubiquitin-dependent degradation counterbalanced by USP7 within PML nuclear bodies, preventing unscheduled nuclease activity (PMID:41002028). Biallelic SLX4 mutations cause Fanconi anemia subtype FA-P, and its essential ICL-repair function maps to the N-terminal XPF-ERCC1-binding region (PMID:21240275, PMID:21240277, PMID:21240276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established the founding biochemical activity of the Slx1-Slx4 pair: that Slx4 is an activating partner converting Slx1 into a functional structure-specific endonuclease, defining the scaffold-plus-nuclease paradigm.

    Evidence Reconstituted in vitro endonuclease assays with purified budding and fission yeast Slx1-Slx4 on branched substrates, plus MMS sensitivity genetics

    PMID:12832395 PMID:14528010

    Open questions at the time
    • Did not address human orthologs or the full multi-nuclease toolkit
    • Structural basis of Slx1 activation by Slx4 unresolved
  2. 2007 High

    Linked Slx4 to the DNA damage checkpoint by showing Mec1/Tel1-dependent phosphorylation governs its repair function and that it binds Rad1 and Slx1 mutually exclusively, revealing regulated, partner-switching scaffolding.

    Evidence Phosphosite mutagenesis, SSA genetic epistasis, and reciprocal Co-IP in budding yeast

    PMID:17636031

    Open questions at the time
    • Did not define how phosphorylation alters partner choice mechanistically
    • Mammalian relevance untested at the time
  3. 2009 High

    Defined human SLX4/BTBD12 as the central scaffold coordinating three endonucleases (XPF-ERCC1, MUS81-EME1, SLX1) and identified SLX1-SLX4 as a bona fide Holliday junction resolvase required for ICL repair and HR.

    Evidence Co-IP/MS, in vitro nuclease assays on branched DNA, and siRNA depletion with genotoxin sensitivity/HR readouts across concurrent papers, with Drosophila orthology

    PMID:19595721 PMID:19595722 PMID:19596235 PMID:19596236

    Open questions at the time
    • Recruitment mechanisms to damage sites not defined
    • How specificity among nucleases is achieved unresolved
  4. 2011 High

    Connected SLX4 to human disease and assigned its essential in vivo role, showing biallelic mutations cause Fanconi anemia FA-P and that the SLX4-XPF-ERCC1 interaction is the critical ICL-repair function.

    Evidence Patient-cell genetic complementation and knockout mouse complementation with interaction-deficient mutants

    PMID:21240275 PMID:21240276 PMID:21240277

    Open questions at the time
    • Did not separate the contributions of individual nuclease modules to disease
    • Recruitment route to ICLs not yet defined
  5. 2011 High

    Identified the recruitment mechanism for ICL repair, establishing that the SLX4 UBZ domain reads ubiquitylated FANCD2 to localize SLX4 to crosslink-induced foci.

    Evidence UBZ mutagenesis with Co-IP, foci imaging, and ICL sensitivity in SLX4-null DT40 cells

    PMID:21464321

    Open questions at the time
    • Later work found FANCD2-independent recruitment routes
    • Did not identify the responsible ubiquitin ligase
  6. 2013 High

    Resolved how distinct nuclease modules serve distinct lesions and defined the CDK-regulated SLX-MUS holoenzyme as a cell-cycle-tuned HJ resolution pathway parallel to GEN1.

    Evidence Separation-of-function interaction mutants, in vitro SLX-MUS reconstitution with CDK phosphorylation, and synthetic-lethality epistasis in human cells

    PMID:23093618 PMID:24076221 PMID:24080495

    Open questions at the time
    • Structural basis of CDK-induced SLX-MUS assembly not yet solved
    • Telomeric recruitment mechanism addressed separately
  7. 2013 High

    Defined telomere targeting, showing SLX4 docks on shelterin TRF2 via an HxLxP motif to deliver its nucleases and regulate telomere length and fragility.

    Evidence Crystal structure of the SLX4 TBM-TRF2 TRFH complex, TBM mutagenesis localization, and telomere length/fragility assays across cell lines

    PMID:23994477 PMID:24012755

    Open questions at the time
    • Did not address SUMO-dependent telomere recruitment
    • In vivo nuclease selection at telomeres not fully defined
  8. 2014 High

    Established the biochemical mechanism of ICL unhooking and the minimal activating module, showing FANCD2-ubiquitylation-dependent recruitment and that mini-SLX4 stimulates XPF-ERCC1 dual incisions up to 100-fold.

    Evidence Xenopus egg extract ICL repair with immunodepletion/FANCD2 mutants and in vitro reconstitution of recombinant mini-SLX4-XPF-ERCC1 on fork substrates

    PMID:24726325 PMID:24726326

    Open questions at the time
    • Role of the full-length scaffold beyond the XPF-binding module not addressed
    • Did not resolve regulation in cells
  9. 2014 High

    Revealed two SUMO-related layers of SLX4 function: an intrinsic SUMO E3 ligase activity targeting SLX4 and XPF, and SIM-mediated SUMO chain binding governing localization to fragile sites and ALT telomeres distinct from ICL repair.

    Evidence In vitro SUMOylation with UBC9, SIM/BTB mutagenesis, and SIM-mutant complementation with multiple functional readouts

    PMID:25533185 PMID:25533188

    Open questions at the time
    • Substrate repertoire of the SLX4 SUMO ligase incompletely mapped
    • How SUMO ligase and nuclease scaffold roles are coordinated unclear
  10. 2014 High

    Showed SLX4 is hijacked by pathogen biology, with HIV-1 Vpr binding SLX4 to prematurely activate the MUS81-EME1 nuclease and cause G2/M arrest while dampening type I interferon.

    Evidence Reciprocal Co-IP, Vpr allele structure-function mapping, and siRNA of SLX4/MUS81/EME1 with cell cycle and interferon readouts

    PMID:24412650

    Open questions at the time
    • Did not define the structural basis of Vpr-SLX4 binding
    • Mechanism of interferon suppression unresolved
  11. 2016 High

    Identified BTB-mediated dimerization as a structural requirement for SLX4 assembly, foci formation, and telomeric targeting.

    Evidence Crystal structure of the SLX4 BTB dimer with dimerization-contact mutants tested for localization, ICL sensitivity, and telomere maintenance

    PMID:27131364

    Open questions at the time
    • Did not link dimerization to nuclease activation directly
    • Stoichiometry of the assembled holocomplex unresolved
  12. 2019 High

    Extended SLX4 beyond endonuclease scaffolding to replication-transcription conflict avoidance through a direct RTEL1 interaction.

    Evidence Reciprocal Co-IP, disease-mutation interaction mutants, PLA on nascent DNA, DNA fiber assays, and transcription-inhibition rescue

    PMID:32398829

    Open questions at the time
    • Whether nuclease activity participates in conflict resolution unclear
    • Direct substrate at conflict sites not defined
  13. 2022 High

    Provided the structural mechanism of CDK1-controlled MUS81 engagement, showing phosphorylation folds an SAP domain in SLX4 to confer high-affinity MUS81 binding and relax substrate specificity.

    Evidence In vitro CDK1-cyclin B phosphorylation, crystal structure of phospho-SLX4MBR-MUS81, and nuclease activity assays

    PMID:36288699

    Open questions at the time
    • In vivo timing of the conformational switch not directly visualized
    • Phosphatase counter-regulation not defined
  14. 2023 Medium

    Reframed SLX4 as an organizer of phase-separated nuclear condensates that compartmentalize SUMO-RNF4 signaling and drive downstream modification and TOP1-DPC extraction.

    Evidence Super-resolution imaging with dimerization/SIM mutants, SENP6/RNF4 manipulation, and TOP1-DPC chromatin extraction assays

    PMID:37059091

    Open questions at the time
    • Functional necessity of condensation for endonuclease activity not separated
    • Single-lab observation awaiting orthogonal confirmation
  15. 2025 Medium

    Defined SLX4 protein homeostasis, showing an RNF4 degradation / USP7 stabilization balance within PML bodies that restrains unscheduled nuclease activity in the absence of damage.

    Evidence Co-IP, ubiquitylation and proteasome-inhibition assays, and PML-body protein stability measurements

    PMID:41002028

    Open questions at the time
    • Single lab; degron signal triggering RNF4 not mapped
    • How damage relieves degradation unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple recruitment cues (K63-ubiquitin, SUMO, PAR, TRF2, RTEL1, TopBP1/CIP2A), the SUMO ligase activity, condensate formation, and CDK-regulated nuclease activation are integrated into a single coordinated decision at a given lesion remains unresolved.
  • No unified structural model of the assembled SLX4 holocomplex on substrate
  • Hierarchy and crosstalk among recruitment signals not established
  • In vivo substrate choice between competing pathways (resolution vs dissolution, HR vs MMR) not fully defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 6 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 2 GO:0016740 transferase activity 1
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2
Partners
FANCD2MSH2MUS81RTEL1SLX1TOPBP1TRF2XPF/ERCC4
Complex memberships
SLX-MUS holoenzyme (SLX1-SLX4-MUS81-EME1)SLX1-SLX4 endonucleaseSLX4-XPF-ERCC1Slx4-Rtt107-Dpb11 (yeast)

Evidence

Reading pass · 57 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Human SLX4 (BTBD12) acts as a scaffold that assembles a multiprotein complex with three structure-specific endonucleases: XPF-ERCC1, MUS81-EME1, and SLX1, as well as MSH2/MSH3, TRF2-RAP1, PLK1, and C20orf94. The SLX1-SLX4 module promotes symmetrical cleavage of static and migrating Holliday junctions, identifying SLX1-SLX4 as a Holliday junction resolvase. SLX4 complexes also cleave 3' flap, 5' flap, and replication fork structures. Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin and reduces DSB repair efficiency in vivo. Co-immunoprecipitation/mass spectrometry, in vitro nuclease assays with branched DNA substrates, siRNA depletion with genotoxin sensitivity assays Cell High 19596235
2009 Human SLX1-SLX4 displays robust Holliday junction resolvase activity and 5' flap endonuclease activity. SLX4 binds the XPF (ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair. SLX4 acts as a docking platform for multiple structure-specific endonucleases. Co-immunoprecipitation, in vitro Holliday junction resolution assays, siRNA depletion with MMC sensitivity and 53BP1/γH2AX foci readouts Cell High 19596236
2009 Human SLX4 coordinates three DNA repair nucleases (XPF-ERCC1, MUS81-EME1, SLX1); SLX4 immunoprecipitates show SLX1-dependent nuclease activity toward Holliday junctions and MUS81-dependent activity toward other branched DNA structures. SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF. Depletion of SLX4 causes hypersensitivity to genotoxins causing DSBs and defects in resolution of ICL-induced DSBs, and decreases DSB-induced homologous recombination. Co-immunoprecipitation, in vitro nuclease activity assays on branched DNA substrates, siRNA depletion with genotoxin sensitivity and HR assays Molecular cell High 19595721
2009 Drosophila MUS312 is the ortholog of human BTBD12/SLX4. BTBD12 interacts with SLX1 (conserved interaction from yeast Slx4) and with DNA structure-specific endonucleases including MEI-9-ERCC1, and is required for interstrand crosslink repair in mammalian cells. Sequence analysis, expression pattern comparison, co-immunoprecipitation, ICL repair assays Molecular cell High 19595722
2003 Budding yeast Slx1 and Slx4 form a heteromeric structure-specific endonuclease active on branched DNA substrates (simple-Y, 5'-flap, replication fork structures). Slx1 is stimulated ~500-fold by Slx4 and requires its PHD finger for activity. Slx1-Slx4 cleaves the strand bearing the 5' nonhomologous arm at the branch junction and generates ligatable nicked products. Both subunits are required for MMS resistance. In vitro endonuclease assays with purified proteins and branched DNA substrates, active-site mutagenesis (PHD finger), MMS sensitivity assays Genes & development High 12832395
2003 Fission yeast Slx1-Slx4 forms a structure-specific endonuclease that maintains rDNA copy number by introducing single-strand cuts in duplex DNA on the 3' side of junctions with single-strand DNA. Slx1 associates with chromatin at rDNA repeat loci. Simultaneous loss of Slx1-Slx4 and Rqh1 (RecQ helicase) is lethal. In vitro endonuclease assays, chromatin immunoprecipitation (localization), genetic synthetic lethality analysis Molecular biology of the cell High 14528010
2013 SLX1-SLX4 and MUS81-EME1 define a second pathway (SLX-MUS) of Holliday junction resolution in human cells distinct from GEN1. In response to CDK-mediated phosphorylation at the G2/M transition, SLX1-SLX4 and MUS81-EME1 associate to form a stable SLX-MUS holoenzyme that can be reconstituted in vitro. SLX-MUS is a more efficient HJ resolvase than SLX1-SLX4 alone, coordinating the active sites of two distinct endonucleases. Cell depletion (siRNA), in vitro reconstitution of SLX-MUS complex, Holliday junction cleavage assays, chromosome segregation assays, CDK phosphorylation assays Molecular cell High 24076221
2014 XPF-ERCC1 cooperates with SLX4/FANCP to carry out the unhooking incisions during replication-coupled ICL repair in Xenopus egg extracts. Efficient recruitment of XPF-ERCC1 and SLX4 to the ICL depends on FANCD2 and its ubiquitylation. Xenopus egg extract ICL repair assay, immunodepletion, FANCD2 ubiquitylation mutants Molecular cell High 24726325
2014 Mouse mini-SLX4 (N-terminal domain that only binds XPF-ERCC1) is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold and directs specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 stimulates dual incisions around a DNA crosslink embedded in a synthetic replication fork. In vitro nuclease activity assays with recombinant proteins, complementation of Slx4-deficient mouse cells, synthetic replication fork substrate assays Molecular cell High 24726326
2014 The SLX4 complex acts as a SUMO E3 ligase that SUMOylates SLX4 itself and the XPF subunit of XPF-ERCC1. This activity is mediated by interaction between SLX4 and UBC9 (SUMO-charged E2 conjugating enzyme), requires SUMO-interacting motifs (SIMs) and the BTB domain of SLX4. SLX4 SIMs are dispensable for ICL repair but critical to prevent mitotic catastrophe following common fragile site expression. In vitro SUMOylation assays, identification of SIMs by mutation, UBC9 interaction assays, cell-based complementation with SIM mutants Molecular cell High 25533188
2014 SLX4 binds SUMO-2/3 chains via SUMO-interacting motifs (SIMs). SLX4 SIMs are dispensable for ICL repair but required for processing CPT-induced replication intermediates, suppressing fragile site instability, and localizing SLX4 to ALT telomeres. SUMO binding of SLX4 enhances interactions with RPA, MRE11-RAD50-NBS1, and TRF2. Localization to laser-induced DNA damage requires SIMs, DNA end resection, UBC9, and MDC1. Co-immunoprecipitation, SIM mutant complementation in SLX4-null cells, laser-induced DNA damage localization, genotoxin sensitivity assays Molecular cell High 25533185
2013 SLX4 assembles an endonuclease toolkit at telomeres via direct interaction with TRF2. Crystal structure of the SLX4 TRF2-binding motif (TBM) in complex with TRF2 TRFH domain reveals that TRF2 recognizes a unique HxLxP motif on SLX4. Telomeric localization of SLX4 and its nucleases depends on SLX4-endonuclease and SLX4-TRF2 interactions. SLX4 negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. Crystal structure determination, co-immunoprecipitation, TBM/SLX4 mutant localization assays, telomere length measurement Cell reports High 24012755
2011 SLX4's UBZ domain is required for interaction with ubiquitylated FANCD2 and for SLX4 recruitment to DNA-damage foci generated by ICL-inducing agents. UBZ-deficient SLX4 cells are selectively sensitive to ICL-inducing agents, demonstrating that ubiquitylated FANCD2 recruits SLX4 to damage sites to mediate resolution of recombination intermediates during ICL processing. UBZ domain mutagenesis, co-immunoprecipitation with ubiquitylated FANCD2, immunofluorescence foci assays, genotoxin sensitivity in SLX4-null DT40 cells reconstituted with UBZ mutants Proceedings of the National Academy of Sciences of the United States of America High 21464321
2012 SLX4-dependent XPF-ERCC1 activity is essential for ICL repair but dispensable for repairing TOP1 inhibitor-induced lesions. MUS81-SLX4 interaction is critical for resistance to TOP1 inhibitors but less important for ICL repair. Mutation of SLX4 abrogating SLX1 interaction results in partial sensitivity to both crosslinking agents and TOP1 inhibitors. Complementation of SLX4-null FA-P cells with interaction-deficient SLX4 mutants (each lacking one nuclease interaction), genotoxin sensitivity assays Blood High 23093618
2007 Budding yeast Slx4 is phosphorylated by Mec1 and Tel1 kinases after DNA damage. This phosphorylation is essential for single-strand annealing (SSA) repair. Slx4 is required for Rad1-dependent SSA but not for nucleotide excision repair. Slx4 associates physically with two structure-specific endonucleases, Rad1 and Slx1, in a mutually exclusive manner. Phosphorylation site mutagenesis, genetic epistasis (SSA assay), co-immunoprecipitation showing mutually exclusive Rad1/Slx1 binding, MMS resistance assays Molecular and cellular biology High 17636031
2010 Mec1 (ATR) mediates a key interaction between the fork protein Dpb11 and the DNA repair scaffolds Slx4-Rtt107. Slx4 phosphorylation by Mec1 is required for Slx4-Dpb11 interaction. Mutation of Mec1 phosphorylation sites in Slx4 disrupts interaction with Dpb11 and compromises cellular response to replication stress. Co-immunoprecipitation, phosphorylation site mutagenesis, two-hybrid interaction assays, genotoxin sensitivity assays Molecular cell High 20670896
2014 Cell cycle-dependent phosphorylation of Slx4 by Cdk1 promotes the Dpb11-Slx4 interaction in yeast. In mitosis, additional phosphorylation of Mms4 by Polo-like kinase Cdc5 promotes association of Mus81-Mms4 with the Dpb11-Slx4 complex, thereby activating joint molecule resolution. The DNA damage checkpoint counteracts Mus81-Mms4 binding to the Dpb11-Slx4 complex. Phosphorylation site mutagenesis, Co-immunoprecipitation, cell cycle synchronization, joint molecule resolution assays Genes & development High 25030699
2015 Crystal structure of Candida glabrata Slx1 alone and in complex with the C-terminal region of Slx4 reveals: (1) Slx1 has a compact GIY-YIG nuclease and RING domain arrangement reinforced by a long α-helix; (2) Slx1 forms a stable homodimer that blocks its active site; (3) Slx1-Slx4 interaction is mutually exclusive with Slx1 homodimerization, suggesting a mechanism for Slx1 activation by Slx4 through displacement of the inhibitory homodimer. X-ray crystallography of Slx1 alone and Slx1-Slx4 C-terminal complex Cell reports High 25753413
2021 The SAP domain of SLX4 is critical for efficient and accurate processing of 5'-flap DNA. The SAP domain binds the minor groove of DNA about one turn away from the flap junction, and the 5'-flap is implicated in binding the core domain of SLX1. This binding mode accounts for specific recognition of 5'-flap DNA and specification of cleavage site. Crystal structure determination, biochemical DNA binding and cleavage assays, computational modeling, SAP domain mutagenesis Nucleic acids research High 34181713
2022 CDK1-cyclin B phosphorylates SLX4 residues T1544, T1561, and T1571 in the MUS81-binding region (SLX4MBR). Phosphorylated SLX4MBR relaxes substrate specificity of MUS81-EME1 and stimulates cleavage of replication and recombination structures. Phosphorylation drives folding of an SAP domain in SLX4MBR, which underpins high-affinity interaction with MUS81. Crystal structure of phosphorylated SLX4MBR bound to MUS81 was determined. In vitro CDK1-cyclin B phosphorylation, crystal structure determination, NMR/biochemical analysis of SAP domain folding, MUS81-EME1 nuclease activity assays, Co-IP Cell reports High 36288699
2016 SLX4 dimerizes via its BTB domain. Crystal structure of SLX4 BTB dimer was solved, identifying key dimerization contacts F681 and F708. Disruption of BTB dimerization abrogates nuclear foci formation and telomeric localization of SLX4 and its associated nucleases, and causes defective response to ICL agents and telomere maintenance. Crystal structure determination, BTB dimerization mutants, immunofluorescence localization, genotoxin sensitivity, telomere length assays Nucleic acids research High 27131364
2013 SLX4 forms foci that localize to telomeres in a range of human cell lines. SLX1 is recruited to telomeres by SLX4, and SLX4 is recruited by a motif that binds the shelterin subunit TRF2 directly. TRF2-dependent recruitment of SLX4 prevents telomere damage. SLX4 prevents telomere lengthening and fragility in a manner partially independent of telomere association. Immunofluorescence co-localization with telomere markers, TRF2-binding motif mutagenesis, telomere length assays, telomere fragility assays Cell reports High 23994477
2015 SLX4's first UBZ domain (UBZ-1) binds ubiquitin polymers with a preference for K63-linked chains, while UBZ-2 does not bind ubiquitin in vitro. UBZ-1 is required for SLX4 recruitment to ICL sites and for efficient ICL repair. UBZ-2 is required for Holliday junction resolution in vivo but not ICL repair. Ubiquitin binding assays with K48- and K63-linked chains, ICL site recruitment by immunofluorescence, complementation in murine fibroblasts with UBZ domain mutants, HJ resolution assay Journal of cell science High 24794496
2010 Mec1/Tel1-dependent phosphorylation of Slx4 at Thr113 is required for efficient cleavage of 3' non-homologous (NH) DNA tails by Rad1-Rad10 during single-strand annealing and homologous recombination. Slx4 is recruited to 3' NH tails during DSB repair independently of its phosphorylation. Deletion of both Mec1 and Tel1 severely reduces NH DNA tail cleavage during HR. Phosphorylation site mutagenesis (Thr113Ala), chromatin immunoprecipitation (Slx4 recruitment to DSB), SSA/HR efficiency assays, Mec1/Tel1 double-deletion epistasis DNA repair High 20382573
2005 Budding yeast Slx4 forms a complex with the BRCA1 C-terminal domain protein Rtt107 (Esc4). SLX4 (but not SLX1) is required for Mec1-dependent phosphorylation of Rtt107 in vivo following DNA damage. Slx4 acts as a mediator of DNA damage-dependent phosphorylation of Rtt107 and is required for recovery from alkylation damage independently of Slx1. Co-immunoprecipitation (Slx4-Rtt107 complex), phosphorylation assays in vivo (comparing slx4Δ vs slx1Δ), DNA damage sensitivity assays Molecular biology of the cell High 16267268
2014 HIV-1 Vpr directly interacts with SLX4 and induces premature activation of the SLX4 complex, including recruitment of VPRBP-DDB1-CUL4 E3 ligase and kinase-active PLK1, enhancing DNA cleavage by SLX4-associated MUS81-EME1 endonucleases, resulting in G2/M arrest. Knockdown of SLX4, MUS81, or EME1 inhibits Vpr-induced G2/M arrest. The SLX4 complex also suppresses spontaneous and HIV-1-mediated induction of type 1 interferon. Co-immunoprecipitation (Vpr-SLX4 interaction), siRNA knockdown of SLX4/MUS81/EME1 with G2/M cell cycle analysis, G2/M-arrest-deficient Vpr allele mapping to SLX4 interaction, interferon induction assays Cell High 24412650
2015 Budding yeast Slx4 is recruited to chromatin behind stressed replication forks in a region spatially distinct from the replication machinery. Slx4 complex formation is nucleated by Mec1 phosphorylation of histone H2A, which is recognized by the constitutive Slx4 binding partner Rtt107. Slx4 is essential for recruiting the Mec1 activator Dpb11 behind stressed replication forks, and Slx4 complexes promote full Mec1 activity. Chromatin immunoprecipitation-sequencing behind replication forks, H2A phosphorylation mutant analysis, Dpb11 localization assays The EMBO journal High 26113155
2013 Human SLX4-null cells are synthetically lethal with BLM depletion or GEN1 depletion, due to unprocessed Holliday junctions causing dysfunctional mitosis. In vivo HJ resolution depends on both SLX4-associated MUS81-EME1 and SLX1 acting in concert within the SLX4 scaffold context. SLX4-null cells, double siRNA depletion (SLX4 + BLM or GEN1), mitotic phenotype analysis, epistasis analysis of SLX4-associated nucleases Cell reports High 24080495
2019 SLX4 directly interacts with the DNA helicase RTEL1. Both proteins are recruited to nascent DNA and co-localize with active RNA pol II. SLX4 in complex with RTEL1 promotes FANCD2/RNA pol II co-localization. Disrupting the SLX4-RTEL1 interaction leads to DNA replication defects rescued by transcription inhibition, demonstrating that SLX4-RTEL1 interaction prevents replication-transcription conflicts. Co-immunoprecipitation, interaction-deficient mutant identification (cancer/Hoyeraal-Hreidarsson mutations), proximity ligation assay for nascent DNA co-localization, DNA fiber assays, transcription inhibition rescue Nature structural & molecular biology High 32398829
2023 SLX4 dimerization and SUMO-SIM interactions drive the assembly of SLX4 membraneless condensates (nanocondensates) in the nucleus. SLX4 compartmentalizes the SUMO-RNF4 signaling pathway. SENP6 and RNF4 regulate assembly and disassembly of SLX4 condensates, respectively. SLX4 condensation triggers SUMOylation and ubiquitylation of selected proteins and induces ubiquitylation and chromatin extraction of topoisomerase 1 DNA-protein cross-links and nucleolytic degradation of newly replicated DNA. Super-resolution microscopy, condensate formation assays with dimerization/SIM mutants, SENP6/RNF4 manipulation, topoisomerase 1-DPC chromatin extraction assays Molecular cell High 37059091
2015 SLX4 associates with telomeres throughout the cell cycle, peaking in late S phase and under genotoxic stress. Disruption of SLX4's interaction with TRF2 or SLX1 independently causes telomere fragility. The SLX1-SLX4 complex processes a variety of telomeric joint molecules in vitro. SLX1-SLX4 nucleolytic activity is negatively regulated by telomeric DNA-binding proteins TRF1 and TRF2, and suppressed by BLM helicase in vitro. Cell cycle-synchronized ChIP for SLX4 localization, TRF2-interaction and SLX1-interaction mutants, in vitro telomeric joint molecule processing assays, telomere fragility assays Nucleic acids research High 25990736
2015 SLX4 is recruited to sites of ICL induction in human cells. The first UBZ domain (UBZ-1) but not UBZ-2 is required for recruitment to ICL sites. SLX4 recruitment to ICLs does not require ubiquitylation of FANCD2 or the E3 ligases RNF8, RAD18, or BRCA1 (based on individual depletions). Immunofluorescence of SLX4 at ICL sites (psoralen/UVA), UBZ deletion mutants, siRNA knockdown of FANCD2/RNF8/RAD18/BRCA1 Journal of cell science Medium 24794496
2021 RNF168 E3 ligase is a critical factor for mitomycin C-induced SLX4 foci formation. RNF168 and SLX4 co-localize in MMC-induced ubiquitin foci. Accumulation of SLX4 at psoralen-laser ICL tracks or of endogenous SLX4 at ICL sites is dependent on RNF168. RNF168 is epistatic with SLX4 in promoting MMC tolerance. siRNA screen, immunofluorescence co-localization, laser ICL track assays, epistasis analysis for MMC tolerance Cell reports Medium 34706224
2019 SLX4IP acts as a regulatory factor binding SLX4 and XPF-ERCC1 simultaneously; disruption of one interaction also disrupts the other. SLX4IP-SLX4-XPF-ERCC1 binding maintains SLX4IP protein stability and promotes SLX4-XPF-ERCC1 interaction after DNA damage. Depletion of SLX4IP sensitizes cells to ICL-inducing agents. Co-immunoprecipitation, domain interaction mapping, SLX4IP depletion with ICL sensitivity and cell cycle assays Nucleic acids research Medium 31495888
2019 In vitro structural and biochemical analysis of fungal Slx1-Slx4: A new protein interface on Slx1 binds the non-cleaved arm of branched DNAs. DNA binding at this site promotes a disorder-to-order transition near the active site, acting as a safety mechanism ensuring cleavage only when the interface is occupied. This binding mode explains how Slx1 cuts toward the 3' end away from branch points and cleaves various DNA structures. X-ray crystallography of Slx1-DNA complexes, biochemical DNA binding and cleavage assays, mutagenesis of the new binding interface, computational modeling Nucleic acids research Medium 31584081
2016 Crystal structure of S. pombe Slx1 C-terminal zinc finger domain in complex with the C-terminal helix-turn-helix domain of Slx4 was determined. The structure reveals a conserved Slx1-Slx4 binding mechanism. Slx1 C-terminal domain is an atypical RING finger required for Slx1-Slx4 interaction. The C-terminal tail of S. pombe Slx1 contains a SUMO-interacting motif (SIM) that recognizes Pmt3 (S. pombe SUMO), suggesting SUMO-dependent recruitment. X-ray crystallography, SUMO binding assays Scientific reports Medium 26787556
2015 SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites. Three SIMs in SLX4 are required for SUMO-2 binding and covalent SLX4 SUMOylation; SIM mutants fail to accumulate at laser-induced DNA damage sites and are absent from PML nuclear bodies. PARylation additionally participates in SLX4 recruitment to DNA damage. SIM mutagenesis, immunofluorescence at laser-induced damage, SUMO-2 co-immunoprecipitation, PARP inhibitor treatment EMBO reports Medium 25722289
2025 RNF4 ubiquitin E3 ligase is associated with SLX4 and is responsible for ubiquitin-dependent proteasomal degradation of excessive SLX4 under normal conditions. PML nuclear bodies promote SLX4 stability, where the deubiquitinase USP7 maintains SLX4 protein levels. This RNF4/USP7 balance within PML NBs regulates SLX4 protein homeostasis to prevent uncontrolled nuclease activity in the absence of DNA damage. Co-immunoprecipitation (RNF4-SLX4), ubiquitylation assays, proteasome inhibition, PML body localization, SLX4 protein stability measurements Nucleic acids research Medium 41002028
2025 Human TopBP1 promotes MiDAS (mitotic DNA synthesis) through recruitment of SLX4 to sites of underreplicated DNA marked by FANCD2. TopBP1-K704 and SLX4-T1260 residues, along with SLX4 SUMO-interaction motifs, are required for SLX4 recruitment to TopBP1 foci in mitosis. Recruitment of SLX4 to TopBP1 foci is important to prevent transmission of DNA damage to daughter cells. Immunofluorescence co-localization, point mutant analysis (TopBP1-K704, SLX4-T1260), siRNA depletion, mitotic DNA synthesis assays Communications biology Medium 40615546
2019 WRNIP1 protects reversed replication forks from SLX4-mediated endonucleolytic cleavage at the junction point. This function is specific to the shorter WRNIP1 variant and is independent of BRCA2-dependent fork protection. siRNA depletion of SLX4 and WRNIP1, DNA fiber assays, epistasis analysis iScience Medium 31654852
2021 CIP2A-TOPBP1 form filamentous structures at sites of incomplete DNA replication during mitosis and facilitate recruitment of the SMX tri-nuclease complex members SLX4, MUS81, and XPF-ERCC1 to these structures. The unstructured C-terminal domain of CIP2A is essential for CIP2A-TOPBP1 filament formation and SMX recruitment. SLX4 is crucial for genome stability in BRCA2-deficient cells. Immunofluorescence, CIP2A domain mutants, siRNA depletion of CIP2A/SLX4, BRCA2-null cell survival assays Nature communications Medium 41330930
2022 SLX4-XPF is required for Tus-Ter-induced homologous recombination at a site-specific chromosomal DNA-protein replication fork barrier, but not for error-free HR induced by a replication-independent DSB. SLX4-XPF also contributes to DSB-induced long-tract gene conversion (break-induced replication). SLX4-XPF can process DNA-protein replication fork barriers. Slx4 and Xpf mouse mutants (interaction-defective), site-specific Tus-Ter replication fork barrier system, HR assays, ICL/DPC sensitivity assays Nature structural & molecular biology Medium 35941380
2021 Abraxas restricts SLX4/MUS81 recruitment to CPT-induced damage sites by counteracting K63-linked ubiquitin modification. Uncontrolled SLX4/MUS81 loading due to Abraxas deficiency leads to excessive end resection and increased break-induced replication via RAD52- and POLD3-dependent, RAD51-independent BIR. siRNA depletion of Abraxas/SLX4/MUS81, K63-ubiquitin ChIP, RAD52/POLD3 epistasis analysis, mitotic DNA synthesis assays Nature communications Medium 34272385
2019 The SLX4 complex promotes resolution of recombination intermediates that counteracts BLM-TOP3A-RMI (BTR) complex-mediated dissolution during ALT telomere synthesis. SLX4-SLX1-ERCC4 promotes resolution of recombination intermediates resulting in telomere exchange without telomere extension, opposing BTR-dependent conservative synthesis. Depletion of BTR and SLX4 complex components, telomere synthesis assays (BrdU-EdU), telomere exchange (T-SCE) assays, epistasis analysis The EMBO journal Medium 28877996
2019 RAD52 and SLX4 mediate distinct post-replicative DNA repair processes at ALT telomeres; RAD52 is dispensable for DSB-induced telomere synthesis while SLX4 is dispensable for RAD52-mediated ALT telomere synthesis in G2. Combined SLX4 and RAD52 loss results in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity, demonstrating non-epistatic roles. CRISPR KO of SLX4, RAD52, double KO; telomere synthesis assays, telomere FISH, mitotic analysis Genes & development Medium 30692206
2024 Polyubiquitinated PCNA (polyUb-PCNA) accumulates SLX4 at ALT telomeres through SLX4's ubiquitin-binding domain, increasing telomere damage. This polyUb-PCNA-SLX4 axis triggers break-induced replication at telomeres and common fragile sites. SLX4 depletion reduces ALT-associated PML bodies and mitotic DNA synthesis at telomeres. RAD18/USP1/ATAD5 depletion, SLX4 ubiquitin-binding domain mutants, APB formation assays, mitotic DNA synthesis assays Nucleic acids research Medium 39291733
2011 Biallelic mutations in SLX4 cause Fanconi anemia subtype FA-P. The cellular defects in patient cells (hypersensitivity to ICL-inducing agents, chromosomal instability) are complemented by wild-type SLX4, establishing SLX4 as an essential component of the FA-BRCA genome maintenance pathway. Genetic complementation of patient cells with wild-type SLX4, chromosomal instability assays, ICL sensitivity assays Nature genetics High 21240275 21240277
2011 Mouse Btbd12/Slx4 knockout phenocopies Fanconi anemia. Genetic complementation reveals a crucial requirement for Btbd12 to interact with Xpf-Ercc1 to promote crosslink repair, placing SLX4-XPF-ERCC1 interaction as essential for ICL repair in vivo. Knockout mouse generation, genetic complementation with interaction-deficient Btbd12 mutant (XPF-binding domain disrupted), ICL sensitivity assays, chromosomal instability measurement Nature genetics High 21240276
2022 SLX4 interacts with MSH2 via an MSH2-interacting peptide (SHIP box) that drives interaction with both MutSβ (MSH2-MSH3) and MutSα (MSH2-MSH6). The MSH2 binding domain is dispensable for ICL repair but mediates inhibition of MutSα-dependent mismatch repair by SLX4. SHIP box mutagenesis, Co-immunoprecipitation with MSH2/MSH6/MSH3, MMR reporter assays, MMC complementation assays Nucleic acids research Medium 35166826
2015 Budding yeast Slx4 limits checkpoint signaling at persistent DSBs and uncapped telomeres by reducing Rad9 binding near irreparable DSBs, requiring Rtt107 and Dpb11 interaction. In slx4Δ cells, Rad9 binding near the DSB is increased, causing robust checkpoint signaling and slower 5' strand resection. Chromatin immunoprecipitation (Slx4, Rad9), checkpoint signaling assays (Rad53 phosphorylation), 5' strand resection measurement, double mutant (slx4Δ sae2Δ) analysis Nucleic acids research Medium 26490958
2019 In Xenopus egg extracts, SLX1 is not required for ICL repair. The MLR domain of SLX4 is crucial for XPF-ERCC1 recruitment and also has an unanticipated function in recruiting SLX4 itself to the site of ICL damage. All essential SLX4 domains for ICL repair are located in the N-terminal half of the protein. Xenopus egg extract ICL repair assay, SLX4 domain deletion mutants reconstituting immunodepleted extracts, SLX1 immunodepletion Nucleic acids research Medium 30576517
2015 Physical interaction between SLX4 and XPF requires a specific SLX4 region. The global minor SLX4 allele Y546C is defective in XPF interaction and cannot complement Fancp knockout cells for ICL-induced cytotoxicity or chromosomal aberrations. Several atypical XP phenotype-causing XPF missense mutations in the SLX4-interacting region cause XPF protein instability. Co-immunoprecipitation of SLX4-XPF interaction with alanine scanning mutants, complementation assays in Fancp knockout mouse cells, immunoprecipitation of XP-associated XPF mutants DNA repair Medium 26453996
2014 MUS81 point mutations that abolish interaction with SLX4 scaffold were identified. These MUS81 mutants fully rescued MMC hypersensitivity in MUS81 knockout murine cells but failed to rescue two human cell lines defective in MUS81, supporting an SLX4-dependent role for MUS81 in ICL repair in human cells. MUS81 point mutagenesis to disrupt SLX4 binding, Co-immunoprecipitation, MMC survival complementation in murine and human MUS81-deficient cells DNA repair Medium 25224045
2012 hSNM1B/Apollo co-immunoprecipitates with SLX4 (FANCP). SLX4 depletion reduces hSNM1B/Apollo nuclear foci formation and cellular TRF2 levels. Double knockdown of hSNM1B/Apollo and FANCP/SLX4 demonstrates epistatic interaction in ICL repair. Co-immunoprecipitation of hSNM1B/Apollo with SLX4, siRNA double knockdown epistasis, immunofluorescence for nuclear foci Human molecular genetics Low 22907656
2021 SLX4 cooperates with MUS81 to introduce DSBs after replication stress but also counteracts pathological targeting of demised replication forks by GEN1. This SLX4 function preventing GEN1 access to fork intermediates is independent of SLX4 interaction with endonucleases; ectopic expression of the HJ-binding protein RuvA inhibits DSBs in SLX4-deficient cells by preventing GEN1 chromatin association. siRNA depletion with SLX4 interaction mutants, RuvA ectopic expression rescue, γH2AX and GEN1 chromatin association assays Scientific reports Low 28290553
2021 SLX4-XPF functions as an upstream factor for accumulation of DDR proteins (ATR, FANCD2) at lacO/LacI-induced replication fork barriers on human chromosomes. The SLX4-ATR axis represses anaphase abnormalities induced by LacI binding. ATR and FANCD2 are interdependently recruited downstream of SLX4-XPF. LacI/lacO replication fork barrier system, siRNA depletion of SLX4/XPF/ATR/FANCD2, immunofluorescence of DDR proteins at lacO sites, mitotic segregation assays The Journal of cell biology Medium 33347546
2021 PARP1 controls SLX4 recruitment to telomeres through its poly(ADP-ribosyl)ation activity; PARP1 depletion reduces SLX4 telomeric localization, which is rescued by wild-type but not catalytically inactive PARP1. SLX4 depletion elongates telomere length, and combined SLX4/PARP1 insufficiency further elongates telomeres and reduces telomere sister chromatid exchange. Immunofluorescence telomere co-localization, catalytically inactive PARP1 rescue, Q-FISH telomere length measurement, T-SCE assay Life sciences Low 33945829

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 378 19596235
2009 Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell 344 19596236
2011 Mutations of the SLX4 gene in Fanconi anemia. Nature genetics 281 21240275
2009 Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Molecular cell 275 19595721
2013 Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Molecular cell 261 24076221
2014 XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Molecular cell 255 24726325
2011 SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nature genetics 244 21240277
2014 Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell 179 24412650
2003 Slx1-Slx4 is a second structure-specific endonuclease functionally redundant with Sgs1-Top3. Genes & development 174 12832395
2011 Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nature genetics 172 21240276
2011 Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proceedings of the National Academy of Sciences of the United States of America 168 21464321
2009 Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific endonucleases in DNA repair and recombination. Molecular cell 147 19595722
2012 Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4. Blood 144 23093618
2017 BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres. The EMBO journal 140 28877996
2014 Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Molecular cell 122 24726326
2013 Human GEN1 and the SLX4-associated nucleases MUS81 and SLX1 are essential for the resolution of replication-induced Holliday junctions. Cell reports 122 24080495
2014 The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. Molecular cell 118 25533188
2014 Roles of SLX1-SLX4, MUS81-EME1, and GEN1 in avoiding genome instability and mitotic catastrophe. Genes & development 116 24831703
2003 Slx1-Slx4 are subunits of a structure-specific endonuclease that maintains ribosomal DNA in fission yeast. Molecular biology of the cell 105 14528010
2013 SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell reports 99 24012755
2019 RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening. Genes & development 98 30692206
2007 Phosphorylation of Slx4 by Mec1 and Tel1 regulates the single-strand annealing mode of DNA repair in budding yeast. Molecular and cellular biology 88 17636031
2010 DNA damage signaling recruits the Rtt107-Slx4 scaffolds via Dpb11 to mediate replication stress response. Molecular cell 83 20670896
2014 A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Genes & development 82 25030699
2013 Combinatorial regulation of meiotic holliday junction resolution in C. elegans by HIM-6 (BLM) helicase, SLX-4, and the SLX-1, MUS-81 and XPF-1 nucleases. PLoS genetics 81 23901331
2013 Localization-dependent and -independent roles of SLX4 in regulating telomeres. Cell reports 78 23994477
2010 GEN1/Yen1 and the SLX4 complex: Solutions to the problem of Holliday junction resolution. Genes & development 76 20203129
2005 Slx4 regulates DNA damage checkpoint-dependent phosphorylation of the BRCT domain protein Rtt107/Esc4. Molecular biology of the cell 74 16267268
2014 Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Molecular cell 72 25533185
2011 Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis. PLoS genetics 65 21655083
2002 Role of SGS1 and SLX4 in maintaining rDNA structure in Saccharomyces cerevisiae. Current genetics 61 12228808
2015 SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic acids research 59 25990736
2012 Distinct roles of Mus81, Yen1, Slx1-Slx4, and Rad1 nucleases in the repair of replication-born double-strand breaks by sister chromatid exchange. Molecular and cellular biology 58 22354996
2015 SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites. EMBO reports 56 25722289
2010 Mec1/Tel1-dependent phosphorylation of Slx4 stimulates Rad1-Rad10-dependent cleavage of non-homologous DNA tails. DNA repair 48 20382573
2023 Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair. Molecular cell 46 37059091
2018 SLX4: multitasking to maintain genome stability. Critical reviews in biochemistry and molecular biology 46 30284473
2014 Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia. Journal of cell science 45 24794496
2005 Slx4 becomes phosphorylated after DNA damage in a Mec1/Tel1-dependent manner and is required for repair of DNA alkylation damage. The Biochemical journal 44 15975089
2011 FANCP/SLX4: a Swiss army knife of DNA interstrand crosslink repair. Cell cycle (Georgetown, Tex.) 43 21527828
2020 SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations. Nature structural & molecular biology 42 32398829
2016 Activation of the DNA Damage Response Is a Conserved Function of HIV-1 and HIV-2 Vpr That Is Independent of SLX4 Recruitment. mBio 38 27624129
2015 Slx4 and Rtt107 control checkpoint signalling and DNA resection at double-strand breaks. Nucleic acids research 38 26490958
2014 G2/M cell cycle arrest correlates with primate lentiviral Vpr interaction with the SLX4 complex. Journal of virology 38 25320300
2015 Assembly of Slx4 signaling complexes behind DNA replication forks. The EMBO journal 37 26113155
2015 Structural and Mechanistic Analysis of the Slx1-Slx4 Endonuclease. Cell reports 36 25753413
2013 Assessment of SLX4 Mutations in Hereditary Breast Cancers. PloS one 35 23840564
2016 SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr). The Journal of biological chemistry 34 27354282
2006 Rad22Rad52-dependent repair of ribosomal DNA repeats cleaved by Slx1-Slx4 endonuclease. Molecular biology of the cell 34 16467377
2016 Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation. International journal of radiation oncology, biology, physics 32 27084631
2019 SLX4IP acts with SLX4 and XPF-ERCC1 to promote interstrand crosslink repair. Nucleic acids research 31 31495888
2008 Mutants defective in Rad1-Rad10-Slx4 exhibit a unique pattern of viability during mating-type switching in Saccharomyces cerevisiae. Genetics 29 18579504
2005 Indirect evidence from DNA sequence diversity for genetic degeneration of the Y-chromosome in dioecious species of the plant Silene: the SlY4/SlX4 and DD44-X/DD44-Y gene pairs. Journal of evolutionary biology 29 15715840
2011 Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer. Breast cancer research and treatment 26 21805310
2019 The role of SLX4 and its associated nucleases in DNA interstrand crosslink repair. Nucleic acids research 25 30576517
2012 The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4. Human molecular genetics 24 22907656
2021 Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability. Critical reviews in biochemistry and molecular biology 23 33596761
2021 Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability. Frontiers in genetics 23 34804132
2012 Whole exome sequencing reveals uncommon mutations in the recently identified Fanconi anemia gene SLX4/FANCP. Human mutation 23 23033263
2021 Structure specific DNA recognition by the SLX1-SLX4 endonuclease complex. Nucleic acids research 22 34181713
2019 WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage. iScience 22 31654852
2016 Slx4 scaffolding in homologous recombination and checkpoint control: lessons from yeast. Chromosoma 22 27165041
2022 Phosphorylation of the DNA repair scaffold SLX4 drives folding of the SAP domain and activation of the MUS81-EME1 endonuclease. Cell reports 21 36288699
2012 Analysis of the novel fanconi anemia gene SLX4/FANCP in familial breast cancer cases. Human mutation 21 22911665
2014 Nuclease delivery: versatile functions of SLX4/FANCP in genome maintenance. Molecules and cells 19 24938228
2012 Low prevalence of SLX4 loss-of-function mutations in non-BRCA1/2 breast and/or ovarian cancer families. European journal of human genetics : EJHG 19 23211700
2022 The structure-specific endonuclease complex SLX4-XPF regulates Tus-Ter-induced homologous recombination. Nature structural & molecular biology 18 35941380
2016 Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex. Nucleic acids research 18 27131364
2014 Identification and characterization of MUS81 point mutations that abolish interaction with the SLX4 scaffold protein. DNA repair 18 25224045
2015 Termination of Replication Stress Signaling via Concerted Action of the Slx4 Scaffold and the PP4 Phosphatase. Genetics 17 26362319
2021 Abraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage. Nature communications 16 34272385
2021 SLX4-XPF mediates DNA damage responses to replication stress induced by DNA-protein interactions. The Journal of cell biology 14 33347546
2016 Budding Yeast SLX4 Contributes to the Appropriate Distribution of Crossovers and Meiotic Double-Strand Break Formation on Bivalents During Meiosis. G3 (Bethesda, Md.) 14 27172214
2015 Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations. DNA repair 14 26453996
2024 Polyubiquitinated PCNA triggers SLX4-mediated break-induced replication in alternative lengthening of telomeres (ALT) cancer cells. Nucleic acids research 13 39291733
2019 Recognition and processing of branched DNA substrates by Slx1-Slx4 nuclease. Nucleic acids research 13 31584081
2015 The Slx4-Dpb11 scaffold complex: coordinating the response to replication fork stalling in S-phase and the subsequent mitosis. Cell cycle (Georgetown, Tex.) 13 25496009
2012 Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families. BMC cancer 13 22401137
2014 How SLX4 cuts through the mystery of HIV-1 Vpr-mediated cell cycle arrest. Retrovirology 12 25496524
2012 Sequencing analysis of SLX4/FANCP gene in Italian familial breast cancer cases. PloS one 12 22383991
2021 RNF168 E3 ligase participates in ubiquitin signaling and recruitment of SLX4 during DNA crosslink repair. Cell reports 11 34706224
2017 SLX4 Prevents GEN1-Dependent DSBs During DNA Replication Arrest Under Pathological Conditions in Human Cells. Scientific reports 11 28290553
2022 SLX4 dampens MutSα-dependent mismatch repair. Nucleic acids research 10 35166826
2014 Conditional genetic interactions of RTT107, SLX4, and HRQ1 reveal dynamic networks upon DNA damage in S. cerevisiae. G3 (Bethesda, Md.) 9 24700328
2025 TopBP1 coordinates DNA repair synthesis in mitosis via recruitment of the nuclease scaffold SLX4. Communications biology 6 40615546
2023 PARP Inhibitors and Proteins Interacting with SLX4. Cancers 6 36765954
2020 Chromosome 16p13.3 Contiguous Gene Deletion Syndrome including the SLX4, DNASE1, TRAP1, and CREBBP Genes Presenting as a Relatively Mild Rubinstein-Taybi Syndrome Phenotype: A Case Report of a Saudi Boy. Case reports in genetics 6 32181026
2014 Crossover recombination mediated by HIM-18/SLX4-associated nucleases. Worm 6 25057454
2023 Localization and expression of SLX4 in the testis of sterile male cattle-yak. Reproduction in domestic animals = Zuchthygiene 5 36880652
2021 PARP1 modulates telomere sister chromatid exchange and telomere length homeostasis by regulating telomere localization of SLX4 in U2OS cells. Life sciences 5 33945829
2016 Crystal structure and SUMO binding of Slx1-Slx4 complex. Scientific reports 5 26787556
2015 SLX4: not SIMply a nuclease scaffold? Molecular cell 5 25574947
2015 SLX4 gains weight with SUMO in genome maintenance. Molecular & cellular oncology 4 27308578
2024 In silico analysis of several frequent SLX4 mutations appearing in human cancers. microPublication biology 3 38828439
2023 Protocol for in vitro phosphorylation of the MUS81-binding region of SLX4 using CDK1-cyclin B. STAR protocols 3 36917604
2017 A low-frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (<60 years) and is associated with reduced DNA repair capacity. International journal of cancer 3 29044504
2025 CIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions. Nature communications 2 41330930
2011 Cancel all Hollidays for SLX4 mutations: identification of a new Fanconi anemia subtype, FANCP. Clinical genetics 2 21476996
2025 The Slx4-Rad1-Rad10 nuclease differentially regulates deletions and duplications induced by a replication fork barrier. PLoS genetics 1 40446207
2025 RNF4 and USP7 coordinate spatial regulation of SLX4 stability within the PML nuclear bodies. Nucleic acids research 1 41002028

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