RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly
DNA-damage signaling utilizes a multitude of posttranslational modifiers as molecular switches to regulate cell-cycle checkpoints, DNA repair, cellular senescence, and apoptosis. Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We...
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| Veröffentlicht in: | Cell 2007-11, Vol.131 (5), p.901-914 |
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| creator | Huen, Michael S.Y. Grant, Robert Manke, Isaac Minn, Kay Yu, Xiaochun Yaffe, Michael B. Chen, Junjie |
| description | DNA-damage signaling utilizes a multitude of posttranslational modifiers as molecular switches to regulate cell-cycle checkpoints, DNA repair, cellular senescence, and apoptosis. Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We have solved the X-ray crystal structure of the FHA domain structure at 1.35 Å. We have shown that RNF8 facilitates the accumulation of checkpoint mediator proteins BRCA1 and 53BP1 to the damaged chromatin, on one hand through the phospho-dependent FHA domain-mediated binding of RNF8 to MDC1, on the other hand via its role in ubiquitylating H2AX and possibly other substrates at damage sites. Moreover, RNF8-depleted cells displayed a defective G2/M checkpoint and increased IR sensitivity. Together, our study implicates RNF8 as a novel DNA-damage-responsive protein that integrates protein phosphorylation and ubiquitylation signaling and plays a critical role in the cellular response to genotoxic stress. |
| doi_str_mv | 10.1016/j.cell.2007.09.041 |
| format | Article |
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Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We have solved the X-ray crystal structure of the FHA domain structure at 1.35 Å. We have shown that RNF8 facilitates the accumulation of checkpoint mediator proteins BRCA1 and 53BP1 to the damaged chromatin, on one hand through the phospho-dependent FHA domain-mediated binding of RNF8 to MDC1, on the other hand via its role in ubiquitylating H2AX and possibly other substrates at damage sites. Moreover, RNF8-depleted cells displayed a defective G2/M checkpoint and increased IR sensitivity. 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| subjects | Amino Acid Motifs Binding Sites BRCA1 Protein - metabolism Cell Cycle - radiation effects Cell Cycle Proteins - metabolism Cells, Cultured DNA DNA Damage - physiology DNA-Binding Proteins - chemistry DNA-Binding Proteins - metabolism DNA-Binding Proteins - physiology Histones - metabolism Histones - physiology Humans Intracellular Signaling Peptides and Proteins - metabolism Models, Biological Models, Molecular Nuclear Proteins - physiology Phosphorylation Protein Binding Protein Structure, Tertiary PROTEINS Signal Transduction SIGNALING Trans-Activators - physiology Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases Ubiquitination - physiology |
| title | RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly |
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