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-Structure paper
タイトル | The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 29, Issue 9, Page 881-890, Year 2022 |
掲載日 | 2022年9月1日 |
著者 | Tamara Sijacki / Pablo Alcón / Zhuo A Chen / Stephen H McLaughlin / Shabih Shakeel / Juri Rappsilber / Lori A Passmore / |
PubMed 要旨 | DNA interstrand cross-links are tumor-inducing lesions that block DNA replication and transcription. When cross-links are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which ...DNA interstrand cross-links are tumor-inducing lesions that block DNA replication and transcription. When cross-links are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2-FANCI clamp by the Fanconi anemia core complex. Monoubiquitinated FANCD2-FANCI is locked onto DNA and recruits nucleases that mediate DNA repair. However, it remains unclear how phosphorylation activates this pathway. Here, we report structures of FANCD2-FANCI complexes containing phosphomimetic FANCI. We observe that, unlike wild-type FANCD2-FANCI, the phosphomimetic complex closes around DNA, independent of the Fanconi anemia core complex. The phosphomimetic mutations do not substantially alter DNA binding but instead destabilize the open state of FANCD2-FANCI and alter its conformational dynamics. Overall, our results demonstrate that phosphorylation primes the FANCD2-FANCI clamp for ubiquitination, showing how multiple posttranslational modifications are coordinated to control DNA repair. |
リンク | Nat Struct Mol Biol / PubMed:36050501 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.53 - 4.4 Å |
構造データ | EMDB-15101, PDB-8a2q: EMDB-15102: FANCD2-FANCI complex containing FANCI (FANCI3D) that contains phosphomimetic mutations EMDB-15103: ubiquitinated DNA-bound FANCD2-FANCI3D |
由来 |
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キーワード | DNA BINDING PROTEIN (DNA結合タンパク質) / nucleic acid protein complex (核酸) / DNA clamp (DNAクランプ) / solenoid domains / Fanconi anemia (ファンコーニ貧血) / DNA repair (DNA修復) / DNA damage (DNA修復) / DNA inter strand crosslink / ubiquitination (ユビキチン) / ATR / pathway activation |