BRCA1-independent ubiquitination of FANCD2.
Monoubiquitination of the FANCD2 protein is a key step in the Fanconi anemia (FA) tumor suppressor pathway, coinciding with this molecule's accumulation at sites of genome damage. Strong circumstantial evidence points to a requirement for the BRCA1 gene product in this step. Here, we show that the purified BRCA1/BARD1 complex, ... together with E1 and UbcH5a, is sufficient to reconstitute the monoubiquitination of FANCD2 in vitro. Although siRNA-mediated knockdown of BRCA1 in human cells results in defective targeting of FANCD2 to sites of DNA damage, it does not lead to a defect in FANCD2 ubiquitination. Furthermore, ablation of the RING finger domains of either BRCA1 or BARD1 in the chicken B cell line DT40 also leaves FANCD2 modification intact. Consequently, while BRCA1 affects the accumulation of FANCD2 at sites of DNA damage, BRCA1/BARD1 E3 ligase activity is not essential for the monoubiquitination of FANCD2.
Mesh Terms:
Animals, BRCA1 Protein, Carrier Proteins, Cell-Free System, DNA Damage, Fanconi Anemia, Fanconi Anemia Complementation Group D2 Protein, Gene Expression Regulation, Neoplastic, Hela Cells, Humans, Iron-Binding Proteins, Ligases, Mutation, Nuclear Proteins, Protein Structure, Tertiary, RNA, Small Interfering, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases
Animals, BRCA1 Protein, Carrier Proteins, Cell-Free System, DNA Damage, Fanconi Anemia, Fanconi Anemia Complementation Group D2 Protein, Gene Expression Regulation, Neoplastic, Hela Cells, Humans, Iron-Binding Proteins, Ligases, Mutation, Nuclear Proteins, Protein Structure, Tertiary, RNA, Small Interfering, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases
Mol. Cell
Date: Jul. 01, 2003
PubMed ID: 12887909
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