| 2013 |
FBXL12 is the F-box protein subunit of an SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex that recognizes and polyubiquitylates Ku80 upon its binding to DNA double-strand breaks (DSBs), leading to Ku80 removal from DNA and proteasomal degradation. Fbxl12 was found to be recruited to DSBs in a DSB- and Ku-dependent manner in Xenopus laevis egg extract; immunodepletion of Fbxl12 prevented Cul1 and Skp1 binding to DSBs and blocked Ku80 ubiquitylation. Uniquely, the F-box domain of Fbxl12 was required for binding to both Skp1 and its substrate Ku80. |
Cell-free Xenopus laevis egg extract system, immunodepletion, F-box protein screen for DSB-binding proteins, ubiquitylation assays |
Cell cycle (Georgetown, Tex.) |
High |
23324393
|
| 2008 |
FBXL12 (FBL12) forms an SCF(FBL12) E3 ubiquitin ligase complex and directly ubiquitinates the CDK inhibitor p57KIP2 in a phosphorylation-dependent manner. TGF-β1 stimulation induces p57KIP2 degradation via this pathway in osteoblasts. Inhibition of FBL12 by RNAi suppressed p57KIP2 degradation; a dominant-negative FBL12ΔF mutant increased steady-state p57KIP2 levels and promoted osteoblast differentiation, while wild-type FBL12 inhibited differentiation. |
Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown, dominant-negative overexpression, primary osteoblast differentiation assay |
EMBO reports |
High |
18660753
|
| 2013 |
Fbxl12 mediates the proteasomal degradation of CaMKI (Ca2+/calmodulin-dependent kinase I) via the ubiquitin-proteasome pathway, causing G1 arrest in lung epithelia. Fbxl12-induced CaMKI degradation disrupts cyclin D1/Cdk4 complex assembly and attenuates CaMKI-mediated phosphorylation of p27 at Thr157/Thr198 (human) or Thr170/Thr197 (mouse), altering p27 subcellular localization. Known inducers of G1 arrest increase Fbxl12 levels in cells. |
Overexpression and knockdown of Fbxl12, proteasome inhibitor experiments, p27 phosphorylation site mutagenesis, cell cycle analysis |
Cellular signalling |
Medium |
23707388
|
| 2015 |
FBXL12 interacts specifically with members of the ALDH3 family and mediates their polyubiquitylation, targeting ALDH3 for proteasomal degradation. This activity is essential for trophoblast stem cell (TSC) differentiation during placental development. FBXL12-deficient mice show ALDH3 accumulation in the placenta, impaired junctional zone formation, and a TSC differentiation defect that is phenocopied by forced ALDH3 expression in wild-type TSCs and rescued by ALDH3 inhibitor gossypol. |
Co-immunoprecipitation, in vivo ubiquitination assay, FBXL12 knockout mice, overexpression/rescue experiments in TSCs, ALDH3 inhibitor treatment |
Stem cells (Dayton, Ohio) |
High |
26124079
|
| 2016 |
The SCF(FBXL12) complex targets ALDH3 for degradation in thymocytes. FBXL12 is most abundant in CD4+CD8+ (DP) thymocytes and declines upon differentiation to SP cells. FBXL12-null mice show a differentiation block at the DP-to-SP transition associated with ALDH3 accumulation. This block is cell-autonomous, demonstrated by bone marrow transplants from FBXL12-null donors into wild-type recipients and by fetal thymic organ culture. |
FBXL12 knockout mice, bone marrow transplantation, fetal thymic organ culture, flow cytometry for T-cell subsets, protein level analysis |
Genes to cells : devoted to molecular & cellular mechanisms |
High |
26999371
|
| 2019 |
Fbxl12 is an SCF subunit whose expression is induced by pre-TCR signaling at the β-selection stage of T cell development. The SCF(Fbxl12) complex targets Cdkn1b (p27) for polyubiquitination and proteasomal degradation, promoting cell cycle progression and proliferation of β-selected thymocytes. Fbxl12 and Fbxl1 (induced by Notch) function additively to degrade Cdkn1b. |
Genetic epistasis in mouse T cell development, conditional knockouts, polyubiquitination assays, cell cycle analysis, transcriptional induction assays |
Nature immunology |
High |
31451788
|
| 2023 |
CHK1-mediated phosphorylation of FANCD2 creates a phosphodegron that is recognized by FBXL12, triggering FANCD2 proteasomal degradation at stalled replication forks. This clears FANCD2 from chromatin and promotes replication fork restart under conditions of CYCLIN E- and drug-induced replication stress. Phosphodegron-mutant FANCD2 cannot rescue fork progression in FANCD2-deficient fibroblasts. In the absence of FBXL12, FANCD2 accumulates on chromatin, causing replication stress and excessive DNA damage. FBXL12 depletion sensitizes cancer cells to WEE1 inhibition. |
In vitro reconstitution with phosphodegron mutants, FBXL12 depletion, chromatin fractionation, DNA fiber assay, FANCD2-deficient cell complementation, drug sensitivity assays |
Molecular cell |
High |
37591242
|
| 2024 |
A neddylation/FBXL12-dependent process actively removes loaded Ku molecules from DNA ends throughout the cell cycle, restricting Ku accumulation to ~1–2 molecules per DNA end in cells. This mechanism operates in concert with DNA-PKcs (structural, not kinase activity) and a CtIP/ATM-dependent S-phase mechanism. Misregulation of Ku loading by disrupting FBXL12 leads to impaired transcription near DNA ends. |
FBXL12 depletion, neddylation inhibition, live-cell imaging, ChIP, transcription assays near DSBs |
Cell reports |
Medium |
39058590
|
| 2022 |
Depletion of FBXL12 in G0 (quiescent) cells promotes extensive DNA end resection at DSBs, consistent with FBXL12's role in removing KU70/KU80 from DSBs to regulate the balance between NHEJ and resection-dependent repair pathways. This effect was specifically observed in G0 cells and not in proliferating G1 or G2 cells. |
CRISPR/Cas9 whole-genome screen, FBXL12 depletion, DNA end resection assays in G0 vs cycling cells |
eLife |
Medium |
35575473
|
| 2015 |
An intronic region of Fbxl12 acts as an alternative promoter, producing a short isoform of Fbl12 that lacks the F-box domain (Fbl12ΔF). UV irradiation increases Fbl12ΔF mRNA in cells. Fbl12ΔF can bind full-length Fbl12 and promote its relocalization from nucleus to cytoplasm, potentially modulating SCF(Fbl12) activity. |
Reporter assays for alternative promoter activity, RT-PCR, UV irradiation, co-immunoprecipitation, subcellular fractionation/localization |
Biochemistry and biophysics reports |
Medium |
29124172
|
| 2025 |
FBXL12 catalyzes K63-linked ubiquitylation of Myosin heavy chain 14 (MYH14) in activated microglia, promoting cytoskeletal reorganization and migration. In the context of spinal cord injury, m6A modification of Fbxl12 mRNA specifically promotes FBXL12 synthesis in activated microglia, and FBXL12 overexpression maintains a scar-less healing microglial phenotype, reducing extracellular matrix deposition. |
Multiomics, m6A modification analysis, overexpression in microglia, K63-ubiquitylation assay, migration/cytoskeletal assays, in vivo spinal cord injury model |
Signal transduction and targeted therapy |
Medium |
40830106
|
| 2025 |
FBXL12 mediates ubiquitination of ALDH1A1, and this process is regulated by the sorcin-PAX5 signaling axis. Sorcin sequesters PAX5 in the cytoplasm, reducing FBXL12 expression and ALDH1A1 ubiquitination. Disruption of the sorcin-PAX5 interaction (e.g., by celastrol binding to Cys194 of sorcin) promotes PAX5 nuclear translocation, induces FBXL12 expression, increases ALDH1A1 ubiquitylation, and triggers ferroptosis in pancreatic cancer cells. |
Co-IP, ChIP, luciferase assays, proteomics, FBXL12 expression manipulation, ubiquitination assays, PAX5 translocation imaging |
Journal of hematology & oncology |
Medium |
40055736
|
| 2025 |
CRY1 K151Q/R mutants show enhanced binding to FBXL12 (but not FBXL3) while exhibiting more stability than wild-type CRY1, without increased ubiquitination-linked degradation. This suggests FBXL12 interacts with CRY1 at K151 through a ubiquitination-independent mechanism that influences circadian period by modulating core clock protein interactions. |
Site-directed mutagenesis, luciferase complementation assay (protein-protein interaction), circadian rescue assay in Cry1/2-deficient cells |
International journal of molecular sciences |
Low |
40869282
|