RRC ID 3535
Author Polanowska J, Martin JS, Garcia-Muse T, Petalcorin MI, Boulton SJ.
Title A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites.
Journal EMBO J.
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, 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.
Volume 25(10)
Pages 2178-88
Published 2006-5-17
DOI 10.1038/sj.emboj.7601102
PII 7601102
PMID 16628214
PMC PMC1462971
MeSH Animals BRCA1 Protein / genetics BRCA1 Protein / metabolism* Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Line Chromatin / metabolism DNA Damage* DNA Repair Enzyme Activation Humans Multiprotein Complexes RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Rad51 Recombinase / genetics Rad51 Recombinase / metabolism Signal Transduction / physiology* Ubiquitin / metabolism* Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism
IF 10.557
Times Cited 95
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
C.elegans tm1145 tm853