Article
- The EMBO Journal (2006) 25, 2178 - 2188
- doi:10.1038/sj.emboj.7601102
Published online: 20 April 2006
Subject Category:
A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites
Jolanta Polanowskaa, Julie S Martin, Tatiana Garcia-Muse, Mark IR Petalcorin and Simon J Boulton
- DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, UK
Correspondence to:
Simon J Boulton, DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, UK-South Mimms, Herts EN6 3LD, UK. Tel.: +44 1707 625774; Fax:+44 2072 693801; E-mail: simon.boulton@cancer.org.uk
aPresent address: Institut de Cancerologie de Marseille, UMR599-INSERM, Marseille, France
Received 2 November 2005; Accepted 28 March 2006
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, 
-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.
Keywords:
- BRCA1,
- C. elegans,
- checkpoint,
- DNA damage,
- ubiquitylation
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