Affinage

SLF2

SMC5-SMC6 complex localization factor protein 2 · UniProt Q8IX21

Length
1173 aa
Mass
131.9 kDa
Annotated
2026-06-10
28 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLF2 (the human ortholog of yeast Nse6) is a localization and regulatory subunit of the SMC5/6 genome-stability complex that targets SMC5/6 to distinct genomic and extrachromosomal compartments through two mutually exclusive Nse5/6-like subcomplexes (PMID:25931565, PMID:36373674, PMID:41294034). Its conserved CANIN domain mediates binding to the SMC6 coiled-coil arm and to the Nse5-like partner, and SLF2 also contacts SMC5 arms, positioning it to lock and regulate complex architecture (PMID:32389690). In the chromosomal arm of this system, SLF2 partners with SLF1 and RAD18 to recruit SMC5/6 to DNA lesions and suppress genome instability (PMID:25931565). In the extrachromosomal arm, SLF2 partners with the Nse5-like protein SIMC1, forming an anti-parallel helical dimer that directs SMC5/6 to SUMO-rich PML nuclear bodies and viral replication centers; this SIMC1-SLF2 subcomplex is exclusively responsible for transcriptional silencing of episomal and viral DNA, including unintegrated HIV-1 DNA, polyomavirus replication centers, HBV cccDNA, and plasmids, via a SUMO-dependent mechanism, while being dispensable for recruitment to chromosomal lesions (PMID:33811831, PMID:36373674, PMID:37338350, PMID:41294034). SLF2-dependent silencing is antagonized by HIV-1 Vpr, which depletes SLF2 (PMID:33811831). Consistent with its role in replication and chromosome integrity, SLF2 loss causes replication stress, defective replication through G-quadruplex DNA, loss of sister chromatid cohesion, and impaired CHK1 activation through loss of Claspin (PMID:36333305, PMID:37485814). Biallelic loss-of-function variants in SLF2 cause Atelís Syndrome, a developmental disorder with microcephaly, short stature, and chromosomal instability featuring segmented/dicentric chromosomes and mosaic variegated hyperploidy (PMID:36333305).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2015 High

    Established SLF2 as a physical and functional component of the SMC5/6 recruitment machinery, answering whether an uncharacterized factor links SMC5/6 to DNA lesions.

    Evidence Chromatin mass spectrometry (CHROMASS) during interstrand cross-link repair in Xenopus egg extracts, identifying the SLF1-SLF2-RAD18 complex

    PMID:25931565

    Open questions at the time
    • Did not resolve the structural basis of SLF2 contacts with SMC5/6
    • Did not distinguish chromosomal from extrachromosomal recruitment roles
  2. 2020 Medium

    Mapped the molecular interface SLF2 uses to engage the complex, defining how it physically integrates into SMC5/6.

    Evidence Crosslinking mass spectrometry and electron microscopy identifying the CANIN domain binding NSE5 and the SMC6 coiled-coil arm, with additional SMC5 arm contacts

    PMID:32389690

    Open questions at the time
    • Functional consequence of arm-locking not directly tested
    • Single-study domain assignment without orthogonal in-cell validation
  3. 2021 High

    Revealed an extrachromosomal silencing role by showing SLF2 directs SMC5/6 to unintegrated viral DNA and that a virus has evolved to counteract it.

    Evidence Targeted CRISPR-Cas9 screen, siRNA depletion, ATAC-seq and proteomics in human cells showing SLF2-dependent compaction of HIV-1 DNA antagonized by Vpr

    PMID:33811831

    Open questions at the time
    • Did not define which SLF2 subcomplex mediates viral targeting
    • Mechanism of substrate discrimination not resolved
  4. 2021 Medium

    Linked SLF2 to telomere maintenance, extending its role beyond bulk genome lesions.

    Evidence BioID proximity labeling and ATRX/SLF2 knockout with telomere proteomics showing SLF2-ATRX proximity inhibits telomere exchanges

    PMID:34780483

    Open questions at the time
    • No biochemical reconstitution of telomere exchange inhibition
    • Direct versus indirect ATRX association not established
  5. 2022 High

    Defined the structural and functional logic of two mutually exclusive Nse5/6-like subcomplexes, showing SIMC1-SLF2 targets SUMO-rich PML bodies and viral replication centers while SLF1-SLF2 acts analogously at chromosomal sites.

    Evidence Structural determination, co-IP, proximity proteomics, and structure-based mutagenesis of the SIMC1-SLF2 interface with cellular localization assays

    PMID:36097294 PMID:36373674

    Open questions at the time
    • Did not fully separate the two subcomplexes' functional outputs
    • SUMO-pathway dependence of recruitment not yet dissected
  6. 2022 High

    Connected SLF2 loss to human disease, establishing its physiological importance for chromosome integrity and replication.

    Evidence Patient-derived cell analysis of Atelís Syndrome with chromosomal breakage, replication stress, G4-DNA replication, and sister chromatid cohesion assays

    PMID:36333305

    Open questions at the time
    • Mechanistic link between SLF2 loss and specific cohesion/G4 defects not fully resolved
    • Genotype-phenotype determinants across patients not defined
  7. 2023 Medium

    Extended SLF2-dependent silencing to HBV cccDNA and mapped the C-terminal region required for SMC5/6 recruitment to PML bodies.

    Evidence siRNA screen of PML body genes, co-IP, deletion mutagenesis (residues 590-710), colocalization and cccDNA transcription assays

    PMID:37338350

    Open questions at the time
    • Relationship of this region to the SIMC1-binding interface not reconciled
    • Single-lab domain mapping
  8. 2023 Medium

    Tied SLF2 to checkpoint signaling and tumor suppression, showing its loss impairs CHK1 activation and drives lymphomagenesis with a SUMOylation vulnerability.

    Evidence Unbiased screening, in vitro and in vivo genetic knockout, CHK1 phosphorylation and Claspin readouts, and SUMOylation-inhibitor sensitivity assays

    PMID:37485814

    Open questions at the time
    • Mechanism linking SLF2 to Claspin stability unknown
    • Whether SUMO synthetic lethality generalizes beyond this model untested
  9. 2023 Low

    Indicated that the SLF2 pathway has substrate specificity among extrachromosomal viral DNA forms distinct from other silencing factors.

    Evidence Comparative siRNA knockdown and knockout of SMC5/SMC6/SLF2 versus CAF1 and POLE3 across HIV-1 DNA forms

    PMID:37922361

    Open questions at the time
    • Specificity inferred from differential silencing without direct biochemical substrate characterization
    • Molecular basis of DNA-form discrimination unknown
  10. 2025 Medium

    Resolved the division of labor between the two subcomplexes, demonstrating SIMC1-SLF2 exclusively silences episomal/plasmid DNA via the SUMO pathway independent of PML and is uninvolved in chromosomal lesion recruitment.

    Evidence Genetic depletion of SIMC1/SLF2, plasmid transcription reporters, comparative recruitment assays, and mutagenesis of the SIMC1-SLF2-SMC6 interface

    PMID:41294034

    Open questions at the time
    • How SUMO-dependence operates without PML bodies not mechanistically defined
    • Switch governing subcomplex choice in vivo unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SLF2 selects between its SLF1- and SIMC1-bound states and how that choice is regulated to partition SMC5/6 between chromosomal and extrachromosomal targets remains unresolved.
  • No defined regulatory signal controlling subcomplex assembly
  • No structural model of the full SLF2-bound holocomplex on substrate DNA
  • Mechanism coupling SLF2 to replication-stress and checkpoint outputs incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-73894 DNA Repair 3
Partners
ATRXRAD18SIMC1SLF1SMC5SMC6
Complex memberships
SIMC1-SLF2 (Nse5/6-like) subcomplexSLF1-SLF2 (Nse5/6-like) subcomplexSMC5/6 complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 SLF2 forms a complex with SLF1 and RAD18, and together this complex defines a pathway that recruits the SMC5/6 cohesion complex to DNA lesions, suppressing genome instability. SLF2 was identified by chromatin mass spectrometry (CHROMASS) during DNA interstrand cross-link repair in Xenopus egg extracts. Chromatin mass spectrometry (CHROMASS) in Xenopus egg extracts; protein complex identification during ICL repair Science (New York, N.Y.) High 25931565
2022 SLF2 recruits the SMC5/6 complex to promyelocytic leukemia (PML) nuclear bodies as the second step of a three-step episomal DNA silencing mechanism. This recruitment is dependent on SLF2 (the human ortholog of yeast Nse6) and is required for transcriptional silencing of episomal DNA. Genetic loss-of-function (knockdown/knockout), cellular imaging, functional silencing assays in human cells Nature structural & molecular biology High 36097294
2021 SLF2 recruits the SMC5/6 complex to unintegrated lentiviral (HIV-1) DNA in the nucleus, leading to chromatin compaction and silencing of viral gene expression. SLF2 depletion or SMC5/6 depletion increases viral expression and chromatin accessibility (ATAC-seq). HIV-1 Vpr antagonizes this restriction by depleting SLF2. Targeted CRISPR-Cas9 screen; siRNA knockdown; ATAC-seq; proteomic analysis of host targets Cell host & microbe High 33811831
2022 SLF2 (Nse6 ortholog) forms an anti-parallel helical dimer with SIMC1 (an Nse5-like protein) that resembles the yeast Nse5/6 structure. This SIMC1-SLF2 complex localizes SMC5/6 to polyomavirus replication centers (PyVRCs) at SUMO-rich PML nuclear bodies via SIMC1's SIM motifs and Nse5-like domain. SLF1 binds SLF2 analogously to SIMC1, forming a separate Nse5/6-like complex. Structure-based mutagenesis of the conserved SIMC1-SLF2 interface disrupts SMC5/6 localization to PyVRCs. Structural determination; co-IP; proximity proteomics; structure-based mutagenesis; cellular localization assays eLife High 36373674
2022 Biallelic loss-of-function variants in SLF2 cause a human developmental syndrome (Atelís Syndrome) characterized by microcephaly, short stature, cardiac abnormalities, anemia, and a unique chromosomal instability phenotype with segmented/dicentric chromosomes and mosaic variegated hyperploidy. Patient-derived SLF2-deficient cells show elevated replication stress, reduced ability to replicate through G-quadruplex DNA, and loss of sister chromatid cohesion. Patient-derived cell analysis; chromosomal breakage assays; replication stress assays; G4-DNA replication assay; sister chromatid cohesion analysis Nature communications High 36333305
2020 The NSE6/SLF2 subunit of the human SMC5/6 complex contains a conserved CANIN (Coiled-coil SMC6 And NSE5 INteracting) domain that mediates binding to NSE5 and to the coiled-coil arm of SMC6. hNSE6 also binds hSMC5 arms, suggesting it may lock the SMC5/6 arms and regulate complex dynamics. Crosslinking mass spectrometry (XL-MS); electron microscopy; biochemical interaction mapping Journal of molecular biology Medium 32389690
2023 SLF2 mediates HBV covalently closed circular DNA (cccDNA) entrapment in PML bodies by interacting with the SMC5/6 complex. The region of SLF2 comprising residues 590–710 is required for interaction with and recruitment of the SMC5/6 complex to PML bodies, and the SLF2 C-terminal domain containing this region is necessary for repression of cccDNA transcription. siRNA screen (91 PML body-related genes); co-immunoprecipitation; deletion mutagenesis; fluorescence colocalization; functional transcription assays Journal of virology Medium 37338350
2023 SLF2 deficiency impairs the DNA damage response by causing loss of Claspin (CLSPN) and consequently impairing CHK1 activation. Genetic deletion of Slf2 drives B-cell lymphomagenesis in vivo. SLF2-deficient tumor cells have elevated DNA damage and alterations in the SUMOylation pathway, conferring synthetic lethality to SUMOylation inhibitors. Unbiased screening; genetic KO (in vitro and mouse in vivo); DDR pathway analysis; CHK1 phosphorylation assays; drug sensitivity assays EMBO molecular medicine Medium 37485814
2025 SMC5/6-mediated repression of plasmid/episomal transcription depends exclusively on the SIMC1-SLF2 subcomplex, whereas SLF1/2 is dispensable for this function. SIMC1-SLF2 does not participate in SMC5/6 recruitment to chromosomal DNA lesions, defining functionally distinct roles for the two Nse5/6-like subcomplexes. Plasmid silencing requires a conserved interaction between SIMC1-SLF2 and SMC6, and depends on the SUMO pathway but not PML nuclear bodies. Genetic loss-of-function (SIMC1/SLF2 depletion); plasmid transcription reporter assays; SMC5/6 recruitment assays to DNA damage sites vs. episomal DNA; mutagenesis of SIMC1-SLF2-SMC6 interface eLife Medium 41294034
2021 SLF2 proximity-association with ATRX helps inhibit telomere exchanges. Loss of SLF2 at telomeres causes changes in abundance of chromatin remodelling, DNA replication, and DNA repair factors, including factors implicated in alternative lengthening of telomeres (ALT). Proximity-dependent biotinylation (BioID); ATRX/SLF2 knockout; telomere proteomics PLoS genetics Medium 34780483
2023 SMC5/SMC6/SLF2 show specificity toward unintegrated HIV-1 DNA forms that are distinct from those targeted by CAF1 or POLE3, indicating SLF2 acts as part of a pathway with specificity for particular forms of extrachromosomal viral DNA. siRNA knockdown; gene knockout; comparison of chromatin silencing factor specificity toward different viral DNA forms Science advances Low 37922361

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links. Science (New York, N.Y.) 196 25931565
2006 Identification and characterization of components of a putative petunia S-locus F-box-containing E3 ligase complex involved in S-RNase-based self-incompatibility. The Plant cell 120 17028207
2021 The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr. Cell host & microbe 71 33811831
2007 Comparison of Petunia inflata S-Locus F-box protein (Pi SLF) with Pi SLF like proteins reveals its unique function in S-RNase based self-incompatibility. The Plant cell 57 18024566
2017 Identification of novel mutations in endometrial cancer patients by whole-exome sequencing. International journal of oncology 43 28339086
2022 Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature communications 37 36333305
2015 mRNAs and miRNAs in whole blood associated with lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma after multi-walled carbon nanotube inhalation exposure in mice. Journal of applied toxicology : JAT 35 25926378
2020 Molecular Insights into the Architecture of the Human SMC5/6 Complex. Journal of molecular biology 32 32389690
2022 Smc5/6 silences episomal transcription by a three-step function. Nature structural & molecular biology 30 36097294
2020 The seasonal development dynamics of the yak hair cycle transcriptome. BMC genomics 28 32393236
2017 Discovery of novel heart rate-associated loci using the Exome Chip. Human molecular genetics 28 28379579
2022 The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers. eLife 26 36373674
2021 ATRX proximal protein associations boast roles beyond histone deposition. PLoS genetics 19 34780483
2016 Cullin1-P is an Essential Component of Non-Self Recognition System in Self-Incompatibility in Petunia. Plant & cell physiology 15 27565207
2023 SLF2 Interacts with the SMC5/6 Complex to Direct Hepatitis B Virus Episomal DNA to Promyelocytic Leukemia Bodies for Transcriptional Repression. Journal of virology 14 37338350
2011 Self-incompatibility in Petunia: a self/nonself-recognition mechanism employing S-locus F-box proteins and S-RNase to prevent inbreeding. Wiley interdisciplinary reviews. Developmental biology 10 23801440
2023 Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex. The Plant journal : for cell and molecular biology 7 37191775
2023 POLE3 is a repressor of unintegrated HIV-1 DNA required for efficient virus integration and escape from innate immune sensing. Science advances 7 37922361
2023 MAPKAPK2-centric transcriptome profiling reveals its major role in governing molecular crosstalk of IGFBP2, MUC4, and PRKAR2B during HNSCC pathogenesis. Computational and structural biotechnology journal 6 36817960
2024 NSE5 subunit interacts with distant regions of the SMC arms in the Physcomitrium patens SMC5/6 complex. The Plant journal : for cell and molecular biology 4 38858852
2024 Structural mechanisms of SLF1 interactions with Histone H4 and RAD18 at the stalled replication fork. Nucleic acids research 4 39360622
2023 Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response. EMBO molecular medicine 4 37485814
2011 [A genome-wide screen for promoter-specific sites of differential DNA methylation during human cell malignant transformation in vitro]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 2 21756782
2025 Transgenerational inheritance of hepatic steatosis in mice: sperm methylome is largely reprogrammed and inherited but does not globally influence liver transcriptome. Environmental epigenetics 1 40040952
2025 Integrative single-cell and bulk transcriptomic analysis reveals the landscape of T cell mitotic catastrophe associated genes in esophageal squamous cell carcinoma. Human genomics 1 40883817
2025 SMC5/6-mediated plasmid silencing is directed by SIMC1-SLF2 and antagonized by the SV40 large T antigen. eLife 1 41294034
2025 SMC5/6-Mediated Plasmid Silencing is Directed by SIMC1-SLF2 and Antagonized by LT. bioRxiv : the preprint server for biology 0 40196500
2017 Selecting an appropriate method for expressing S locus F-box-S2 recombinant protein. Biotechnology reports (Amsterdam, Netherlands) 0 28664149

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