The human homolog of yeast BRE1 functions as a transcriptional coactivator through direct activator interactions.
Diverse histone modifications such as acetylation, methylation, and phosphorylation play important roles in transcriptional regulation throughout eukaryotes, and recent studies in yeast also have implicated H2B ubiquitylation in the transcription of specific genes. Here, we report the identification of a functional human homolog, hBRE1, of the yeast BRE1 E3 ubiquitin ligase. hBRE1 specifically increases the global level of H2B ubiquitylation at lysine 120 and enhances activator-dependent transcription. Moreover, reduction of hBRE1 by RNAi decreases endogenous H2B ubiquitylation, activator-dependent transcription, and interestingly, H3-K4 and -K79 methylation. Of special significance, we show that hBRE1 directly interacts with p53 and that it is recruited to the mdm2 promoter in a p53-dependent manner. These studies suggest that hBRE1 is an H2B-specific E3 ubiquitin ligase and that it functions, through direct activator interactions, as a transcriptional coactivator. Importantly, they thus provide a paradigm for BRE1 recruitment and function in both yeast and higher eukaryotes.
Kim
Jaehoon
J
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA.
Hake
Sandra B
SB
Roeder
Robert G
RG
D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D014452:Ubiquitins / Q000378:metabolism
C472168:Bre1 protein, S cerevisiae; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases