A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites
| Autor: | Simon J. Boulton, Julie S. Martin, Mark I.R. Petalcorin, Tatiana García-Muse, Jolanta Polanowska |
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| Rok vydání: | 2006 |
| Předmět: |
DNA Repair
DNA repair DNA damage Ubiquitin-Protein Ligases Article General Biochemistry Genetics and Molecular Biology Cell Line Ubiquitin Animals Humans RNA Small Interfering Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Gene chemistry.chemical_classification DNA ligase General Immunology and Microbiology biology BRCA1 Protein General Neuroscience G2-M DNA damage checkpoint Molecular biology Chromatin Enzyme Activation MRN complex chemistry Multiprotein Complexes biology.protein Rad51 Recombinase DNA Damage Signal Transduction |
| Zdroj: | The EMBO Journal. 25:2178-2188 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.1038/sj.emboj.7601102 |
| Popis: | The BRCA1 tumour suppressor and its heterodimeric partner BARD1 constitute an E3-ubiquitin (Ub) ligase and function in DNA repair by unknown mechanisms. We show here that the Caenorhabditis elegans BRCA1/BARD1 (CeBCD) complex possesses an E3-Ub ligase responsible for ubiquitylation at DNA damage sites following ionizing radiation (IR). The DNA damage checkpoint promotes the association of the CeBCD complex with E2-Ub conjugating enzyme, Ubc5(LET-70), leading to the formation of an active E3-Ub ligase on chromatin following IR. Correspondingly, defects in Ubc5(let-70) or the DNA damage checkpoint genes atl-1 or mre-11 abolish CeBCD-dependent ubiquitylation in vivo. Extending these findings to human cells reveals a requirement for UbcH5c, the MRN complex, gamma-H2AX and a co-dependence for ATM and ATR kinases for BRCA1-dependent ubiquitylation at DNA damage sites. Furthermore, we demonstrate that the DNA damage checkpoint promotes the association between BRCA1 and UbcH5c to form an active E3-Ub ligase on chromatin after IR. These data reveal that BRCA1-dependent ubiquitylation is activated at sites of DNA repair by the checkpoint as part of a conserved DNA damage response. |
| Databáze: | OpenAIRE |
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