期刊
PLOS GENETICS
卷 18, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1010335
关键词
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资金
- NSF/MCBBSF grant [1715822, 2114950]
- NIH [CA178974]
- Deutsche Forschungsgemeinschaft (German Research Foundation) [SFB1074/A03, SFB1506/A05, OS 287/4-1, GRK 2254/C4]
- ''Deutsche Krebshilfe (German Cancer Aid) [70114289]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [TRR81-A12, BO1639/9-1]
- State of Hesse (LOEWE iCANx)
- von BehringRontgen Stiftung [65-0004]
Notch signaling pathway involves RBPJ variants associated with AOS, encoding proteins with compromised DNA binding activity but retained cofactor binding. This mechanism underlies the dysregulation of Notch target genes in AOS phenotypes.
Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian corepressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.
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