A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39607926.
- Also identified by DOI 10.1126/science.adp3025 and PMC identifier 12924673.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Down-regulation of BCL11A protein reverses the fetal (HbF, α<sub>2</sub>γ<sub>2</sub>) to adult (HbA, α<sub>2</sub>β<sub>2</sub>) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for γ-globin gene repression, because an engineered monomer fails to engage a critical co-repressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing and provide opportunities for drug discovery.
Medical subject headings
- Erythroid Cells
- Fetal Hemoglobin
- gamma-Globins
- Protein Multimerization
- Repressor Proteins
- Zinc Fingers