A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites

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Abstract
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, γ‐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.

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