A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites.
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.[1]References
- A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. Polanowska, J., Martin, J.S., Garcia-Muse, T., Petalcorin, M.I., Boulton, S.J. EMBO J. (2006) [Pubmed]
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