Affinage

Showing FAM120B — SAN1 is a alias.

FAM120B

Constitutive coactivator of peroxisome proliferator-activated receptor gamma · UniProt Q96EK7

Length
910 aa
Mass
103.8 kDa
Annotated
2026-06-09
15 papers in source corpus 2 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM120B (SAN1) is a 5' exonuclease that functions in genome maintenance by repairing interstrand DNA cross-links and resolving R-loop-associated DNA damage (PMID:29968717, PMID:34339838). It acts in a Fanconi anemia-independent pathway, as its loss is not epistatic with FANCD2 for cross-link sensitivity, and its catalytic exonuclease activity is essential—a nuclease-dead variant fails to rescue cross-link sensitivity in SAN1-deleted cells (PMID:29968717). SAN1 physically associates with the R-loop-resolving RNA/DNA helicase Senataxin (SETX), an interaction that increases upon cross-link induction and is required to prevent cross-link sensitivity, placing the two proteins in a common pathway (PMID:29968717). Consistent with this role, loss of San1 in mice causes excessive R-loop accumulation, increased DNA damage, ATR and PARP1 activation, G2/M arrest, and impaired cell proliferation (PMID:34339838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2018 High

    Established that FAM120B/SAN1 is a catalytically active 5' exonuclease required for interstrand cross-link resistance, defining its core molecular function in genome maintenance.

    Evidence CRISPR/Cas9 deletion with wild-type versus nuclease-dead re-expression and cell survival/radial chromosome assays in HeLa cells and MEFs

    PMID:29968717

    Open questions at the time
    • Direct biochemical demonstration of exonuclease activity on defined substrates not shown in the timeline
    • Step in cross-link repair at which the nuclease acts is undefined
  2. 2018 Medium

    Identified Senataxin as a physical partner of SAN1 whose interaction increases upon cross-link stress, linking SAN1 to R-loop resolution machinery.

    Evidence Reciprocal Co-immunoprecipitation with Mitomycin C treatment and deletion complementation assays

    PMID:29968717

    Open questions at the time
    • Single-lab Co-IP; interaction interface and direct versus indirect binding unresolved
    • Whether SETX recruits SAN1 or vice versa not determined
  3. 2018 Medium

    Placed SAN1 in a Fanconi anemia-independent cross-link repair pathway through clean genetic epistasis with FANCD2.

    Evidence Genetic epistasis analysis combining SAN1 and FANCD2 loss with ICL sensitivity assays

    PMID:29968717

    Open questions at the time
    • Other pathway components acting with SAN1 not identified
    • Mechanistic relationship to canonical FA-dependent repair undefined
  4. 2021 Medium

    Demonstrated in vivo that SAN1 loss drives R-loop accumulation and replication/DNA-damage stress, extending its role from cross-link repair to R-loop-associated damage resolution in a physiological tissue.

    Evidence CRISPR/Cas9 San1 knockout mice with S9.6 and gammaH2AX immunostaining, cell cycle analysis, and San1-/- AC16 cardiomyocyte line

    PMID:34339838

    Open questions at the time
    • Whether R-loop accumulation is a direct consequence of lost nuclease activity or secondary to defective repair not resolved
    • Tissue specificity of the cardiomyocyte phenotype not explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SAN1 exonuclease activity mechanistically couples to SETX-driven R-loop resolution and cross-link repair at the molecular level remains open.
  • No structural model of SAN1 or the SAN1-SETX complex
  • Direct nucleic acid substrate specificity not biochemically defined
  • Order of events in the FA-independent repair pathway unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 1 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-73894 DNA Repair 2
Partners
SETX

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Human SAN1 (FAM120B) functions as a 5' exonuclease that acts independently of the Fanconi anemia (FA) pathway to confer resistance to interstrand DNA cross-links (ICLs); nuclease-dead SAN1 fails to rescue ICL sensitivity in SAN1-deleted HeLa cells and mouse embryonic fibroblasts, establishing that catalytic exonuclease activity is required for its function. CRISPR/Cas9 deletion, re-expression of wild-type vs. nuclease-dead SAN1, cell survival assays, chromosomal radial formation assays, epistasis with FANCD2 Nature Communications High 29968717
2018 SAN1 (FAM120B) physically binds to Senataxin (SETX), an RNA/DNA helicase that resolves R-loops; this interaction is increased upon ICL-inducing treatment with Mitomycin C, and the SAN1–SETX interaction is required to prevent cross-link sensitivity, placing SAN1 in a pathway with SETX. Co-immunoprecipitation, Mitomycin C treatment, SAN1 deletion complementation assays Nature Communications Medium 29968717
2018 SAN1 (FAM120B) deletion is not epistatic with FANCD2 (a core FA pathway component) for ICL sensitivity, establishing that SAN1 operates in an FA-independent pathway for ICL repair. Genetic epistasis analysis — double deletion/knockdown of SAN1 and FANCD2 combined with ICL sensitivity assays Nature Communications Medium 29968717
2021 Loss of San1 (FAM120B) in mice leads to excessive R-loop accumulation in neonatal cardiomyocyte nuclei, increased DNA damage (γH2AX), activation of ATR and PARP1 hyperactivity, G2/M cell-cycle arrest, and impaired cardiomyocyte proliferation, establishing a role for SAN1 in resolving R-loop-associated DNA damage in cardiomyocytes. CRISPR/Cas9 San1 knockout mice, S9.6 immunostaining for R-loops, γH2AX staining, cell cycle analysis, San1-/- AC16-cardiomyocyte cell line Biochimica et Biophysica Acta. Molecular Basis of Disease Medium 34339838

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proceedings of the National Academy of Sciences of the United States of America 231 20080635
2004 Sir Antagonist 1 (San1) is a ubiquitin ligase. The Journal of biological chemistry 40 15078868
2019 The STING activator c-di-AMP exerts superior adjuvant properties than the formulation poly(I:C)/CpG after subcutaneous vaccination with soluble protein antigen or DEC-205-mediated antigen targeting to dendritic cells. Vaccine 38 31320219
1993 The Saccharomyces cerevisiae Cdc68 transcription activator is antagonized by San1, a protein implicated in transcriptional silencing. Molecular and cellular biology 34 8246972
2011 Nuclear protein quality is regulated by the ubiquitin-proteasome system through the activity of Ubc4 and San1 in fission yeast. The Journal of biological chemistry 26 21324894
2008 Genetic analysis of the spindle checkpoint genes san-1, mdf-2, bub-3 and the CENP-F homologues hcp-1 and hcp-2 in Caenorhabditis elegans. Cell division 22 18248670
2018 A senataxin-associated exonuclease SAN1 is required for resistance to DNA interstrand cross-links. Nature communications 20 29968717
2016 Molecular mass as a determinant for nuclear San1-dependent targeting of misfolded cytosolic proteins to proteasomal degradation. FEBS letters 16 27173001
2016 The San1 Ubiquitin Ligase Functions Preferentially with Ubiquitin-conjugating Enzyme Ubc1 during Protein Quality Control. The Journal of biological chemistry 12 27405755
2021 San1 deficiency leads to cardiomyopathy due to excessive R-loop-associated DNA damage and cardiomyocyte hypoplasia. Biochimica et biophysica acta. Molecular basis of disease 9 34339838
2021 Genome-Wide Regulations of the Preinitiation Complex Formation and Elongating RNA Polymerase II by an E3 Ubiquitin Ligase, San1. Molecular and cellular biology 8 34661445
2021 The San1 Ubiquitin Ligase Avidly Recognizes Misfolded Proteins through Multiple Substrate Binding Sites. Biomolecules 6 34827617
2011 San1-mediated quality control: substrate recognition "sans" chaperones. Molecular cell 5 21211716
2025 TAP-MS analysis of FACT interactions and regulation by a ubiquitin ligase, San1. Biochimica et biophysica acta. Gene regulatory mechanisms 2 39855624
2024 Role of the San1 ubiquitin ligase in the heat stress-induced degradation of nonnative Nup1 in the nuclear pore complex. Genetics 1 38302116

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