Fanconi Anaemia E3 Ligase complex activity is regulated by a druggable metabolite binding site in FANCX
Sharp, M. F.; Gee, Y. S.; Luu, J.; Cowley, K.; Beetham, H.; Langendorf, C. G.; Oakhill, J. S.; Scott, J. W.; Cavero, D.; Minguillon, J.; Che, D.; Baell, J. B.; Deans, A. J.; Surralles, J.; Simpson, K. J.; Crismani, W.
Show abstract
The Fanconi anaemia (FA) DNA repair pathway is an emerging target for precision cancer therapy. Using a high-throughput FANCD2-monoubiquitination assay, we identified a class of small molecules, including MSG010, that inhibit the FA E3 ligase complex in vitro. Because these molecules, and the metabolite, palmitoyl-CoA, are known to engage allosteric drug and metabolite (ADaM) binding site in AMP-activated kinase (AMPK), we hypothesised that a similar pocket exists within the FA complex. Supporting this, long-chain, but not short-chain, fatty acyl-CoA molecules inhibited the FA E3 ligase complex activity, and sequence analysis revealed similarity between the AMPK ADaM site and a WD40 repeat in the FA subunit FANCX. Targeted mutagenesis of this FANCX region disrupted E3 ligase activity or abolished inhibition by MSG010, suggesting the presence of an ADaM-like site in FANCX. Moreover, MSG010 preferentially killed BRCA1-deficient cells in vitro. These findings identify a putative small-molecule binding site in the FA pathway that may be developed further to test for exploitation as anticancer therapeutics.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- TK216 targets microtubules in Ewing sarcoma cells 95%
- Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules 94%
- A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death 94%
Similar papers in this journal
- Identification of regulators of poly-ADP-ribose polymerase (PARP) inhibitor response through complementary CRISPR knockout and activation screens 94%
- Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair 94%
- A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response 93%
Similar papers in this journal
- Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death 93%
- A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells 93%
- Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1 92%
Similar papers in this journal
- Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing 94%
- Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells 93%
- Inhibition of Mycobacterium tuberculosis DosRST two-component regulatory system signaling by targeting response regulator DNA binding and sensor kinase heme 92%
Similar papers in this journal
- Structure-based Design of CDC42 Effector Interaction Inhibitors For the Treatment of Cancer 93%
- Guiding ATR and PARP inhibitor combinations with chemogenomic screens 93%
- Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.