The Human Homolog of Yeast BRE1 Functions as a Transcriptional Coactivator through Direct Activator Interactions

Abstract

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.

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

“…The list of genes suppressed by RNF20 comprises numerous proto-oncogenes and proliferation-related genes, including many that are known to be induced by epidermal growth factor (EGF). Conversely, RNF20 is required for optimal expression and activity of p53, and several studies indicate that the p53 response to DNA damage is significantly attenuated in cells lacking RNF20 [55,61,63]. Consistent with the transcriptomic effect of RNF20 depletion, RNF20 exhibits a variety of in vitro and in vivo biological effects that suggest it may act as a tumor suppressor [61].…”

“…This pathway is conserved from yeast to mammals, and is dependent on a host of additional proteins that converge at the elongating RNA Pol II [41,[49][50][51][52][53][54]. Subsequently, the mammalian orthologs of the yeast Bre1, RNF20 and RNF40, were identified [55,56]. These two proteins form a tight heterodimer that acts as the major E3 ligase responsible for histone H2B monoubiquitylation on K120 in mammalian cells.…”

“…It is also plausible that H2Bub alters chromatin structure in the specific context of those genes and makes it more accessible to the transcription machinery [70]. Alternatively, RNF20 may affect the activity of some transcriptional regulators, especially since it was shown to directly bind and influence the transcriptional activity of the transcription factor and tumor suppressor protein p53 [55]. However, a significant enrichment for specific transcription factor binding motifs in RNF20-dependent genes could not be confirmed (data not shown).…”

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

“…Overexpression and depletion of hBre1 increases and decreases global H2B ubiquitination, respectively. By contrast, ectopic hRAD6A and hRAD6B, human homologues of yRAD6, do not affect H2B ubiquitination or H3 methylation, suggesting that hRAD6 proteins are not cognate E2 enzymes for hBre1 (Kim et al, 2005). In addition to transcriptional coactivation of specific genes (Osley, 2004), Bre1 in Drosophila is required for Notch signaling and histone modification (Bray et al, 2005).…”

“…Additionally, PAF complex is also required for H2B ubiquitination (Ng et al, 2003;Wood et al, 2003b). In humans, the homologue of yeast Bre1 (RNF20), designated as hBre1, acts as an E3 ligase for H2B and promotes its ubiquitination at K120, the equivalent of yeast H2B K123 (Kim et al, 2005;Zhu et al, 2005). Moreover, it has a coactivator function in activator-dependent transcription of several genes.…”