BRCA1 Ubiquitinates RPB8 in Response to DNA Damage
| Autor: | Mamoru Fukuda, Akeri Honda, Ko Sato, Wenwen Wu, Satoko Aratani, Ryosuke Hayami, Tomohiko Ohta, Toshihiro Nakajima, Hiroyuki Nishikawa |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
endocrine system diseases Ultraviolet Rays DNA damage Ubiquitin-Protein Ligases Protein subunit Proteolysis Ubiquitin RNA interference Cell Line Tumor medicine Humans skin and connective tissue diseases Ubiquitins Polymerase Epirubicin Gene knockdown biology medicine.diagnostic_test BRCA1 Protein Tumor Suppressor Proteins RNA DNA-Directed RNA Polymerases Molecular biology Protein Subunits Oncology biology.protein DNA Damage HeLa Cells |
| Zdroj: | Cancer Research. 67:951-958 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-06-3187 |
| Popis: | The breast and ovarian tumor suppressor BRCA1 catalyzes untraditional polyubiquitin chains that could be a signal for processes other than proteolysis. However, despite intense investigations, the mechanisms regulated by the enzyme activity remain only partially understood. Here, we report that BRCA1-BARD1 mediates polyubiquitination of RPB8, a common subunit of RNA polymerases, in response to DNA damage. A proteomics screen identified RPB8 as a protein modified after epirubicin treatment in BRCA1-dependent manner. RPB8 interacted with BRCA1-BARD1 and was polyubiquitinated by BRCA1-BARD1 in vivo and in vitro. BRCA1-BARD1 did not destabilize RPB8 in vivo but rather caused an increase in the amount of soluble RPB8. Importantly, RPB8 was polyubiquitinated immediately after UV irradiation in a manner sensitive to BRCA1 knockdown by RNA interference. Substitution of five lysine residues of RPB8 with arginine residues abolished its ability to be ubiquitinated while preserving its polymerase activity. HeLa cell lines stably expressing this ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity accompanied by up-regulated caspase activity. Our findings suggest that ubiquitination of a common subunit of RNA polymerases is a mechanism underlying BRCA1-dependent cell survival after DNA damage. [Cancer Res 2007;67(3):951–8] |
| Databáze: | OpenAIRE |
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