SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy.
BRCA1, a tumor suppressor gene, is implicated in the repression and activation of transcription via interactions with a diverse range of proteins. The mechanisms regulating the action of BRCA1 are not fully understood. Here, we use the promoters of Gadd45alpha, p27(KIP1) and p21(WAF1/CIP1) to demonstrate that SUMO1 represses transactivation potential of BRCA1 by causing BRCA1 to be released from the promoters and augmenting histone deacetylation via recruitment of histone deacetylase (HDAC) activity. Consistently, silencing of SUMO1 led to recruitment of BRCA1 and release of HDAC1 at the BRCA1 target promoters, and subsequent transcriptional activation of the BRCA1 target genes. Furthermore, a sumoylation-incompetent mutant missing the sumoylation donor site suppressed BRCA1-induced activation of transcription, whereas E2 UBC9 or the dominant-negative mutant UBC9 had no effect, implying that repression of BRCA1-mediated activation of transcription by SUMO1 is independent of sumoylation. Repression of BRCA1-mediated activation of transcription by SUMO1 was reversed by DNA damage by inducing the release of SUMO1 from the Gadd45alpha promoter and the recruitment of BRCA1, along with increased histone acetylation, to enhance activation of transcription. Together, our data provide evidence that SUMO1 plays a role in the activation-repression switch of BRCA1-mediated transcription via modulation of promoter occupancy.
Park
Mi Ae
MA
Department of Biological Sciences & Department of Molecular Science and Technology Ajou University, Suwon, Korea.
Seok
Yeong-Jae
YJ
Jeong
Gajin
G
Lee
Jong-Soo
JS
D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D004249:DNA Damage; D015536:Down-Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D025842:SUMO-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D006655:Histone Deacetylases; D006657:Histones; D009687:Nuclear Proteins; D025842:SUMO-1 Protein; C439070:GADD45A protein, human; D000097642:GADD45 Proteins