Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1.
BRCA1 has been implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. To explore the mechanistic basis for this regulation, a novel human gene, ZBRK1, which encodes a 60 kDa protein with an N-terminal KRAB domain and eight central zinc fingers, was identified by virtue of its interaction with BRCA1 in vitro and in vivo. ZBRK1 binds to a specific sequence, GGGxxx CAGxxxTTT, within GADD45 intron 3 that supports the assembly of a nuclear complex minimally containing both ZBRK1 and BRCA1. ZBRK1 represses transcription through this recognition sequence in a BRCA1-dependent manner. These results thus reveal a novel corepressor function for BRCA1 and provide a mechanistic basis for the biological activity of BRCA1 through sequence-specific transcriptional regulation.
Zheng
L
L
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 78245, USA.
Pan
H
H
Li
S
S
Flesken-Nikitin
A
A
Chen
P L
PL
Boyer
T G
TG
Lee
W H
WH
D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins; D019398:Genes, BRCA1; D016158:Genes, p53; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors; D016335:Zinc Fingers; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097642:GADD45 Proteins; C422407:ZNF350 protein, human