RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.
Mutations affecting the BRCT domains of the breast cancer-associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-gammaH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.
Sobhian
Bijan
B
Dana-Farber Cancer Institute and Department of Genetics and Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Shao
Genze
G
Lilli
Dana R
DR
Culhane
Aedín C
AC
Moreau
Lisa A
LA
Xia
Bing
B
Livingston
David M
DM
Greenberg
Roger A
RA
D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D019313:BRCA1 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C466234:UIMC1 protein, human; D025801:Ubiquitin; D004247:DNA; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases