org Rtf1 Rtf1: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References
Gene name - Rtf1

Synonyms - CG10955

Cytological map position- 58D4-58D4

Function - chromatin modification, signaling

Keywords - modification of chromatin strucure, ubiquitination of histone H2B, regulation of RNA polymerase

Symbol - Rtf1

FlyBase ID: FBgn0034722

Genetic map position - 2R

Classification - Plus-3 domain protein

Cellular location - nuclear



NCBI links: Precomputed BLAST | EntrezGene | UniGene | HomoloGene | PubMed articles
BIOLOGICAL OVERVIEW

The Rtf1 subunit of the Paf1 complex is required for proper monoubiquitination of histone H2B and methylation of histone H3 on lysines 4 (H3K4) and 79 in yeast Saccharomyces cerevisiae. Using RNAi, the role of Rtf1 in histone methylation and gene expression was examined in Drosophila. Drosophila Rtf1 (dRtf1) is required for proper gene expression and development. Furthermore, RNAi-mediated reduction of dRtf1 results in a reduction in histone H3K4 trimethylation levels on bulk histones and chromosomes in vivo, indicating that the histone modification pathway via Rtf1 is conserved among yeast, Drosophila, and human. Recently, it was demonstrated that histone H3K4 methylation mediated via the E3 ligase Bre1 is critical for transcription of Notch target genes in Drosophila. This study demonstrates that the dRtf1 component of the Paf1 complex functions in Notch signaling (Tenney, 2006).

Interplay between transcriptional activators and repressors regulates gene expression by RNA polymerase II (RNA Pol II). In several cases, chromatin structure is implicated in transcriptional activation and repression. Posttranslational methylation of lysines on the N-terminal tails of histones is thought to modulate higher-order chromatin folding and can activate or repress transcription, depending on the residue being methylated, the regulatory protein recruited by the methyl mark, and whether the lysine is mono-, di-, or trimethylated (Tenney, 2006 and references therein).

Histone modifications can be interdependent, such that one modification requires another preexisting modification. Histone H3 methylation at lysines 4 and 79 is catalyzed by the complex of proteins associated with Set1 (COMPASS; the yeast homologue of the mammalian MLL complex and of the Drosophila trithorax complex) and Dot1p, respectively in Saccharomyces cerevisiae. Methylation at these residues requires monoubiquitination of histone H2B at lysine 123 by Rad6/Bre1 (Rad6 is a E2 conjugating enzyme and Bre1 is its E3 ligase). The Paf1 complex indirectly regulates histone methylation through its regulation of H2B monoubiquitination and interaction of COMPASS with RNA Pol II (Tenney, 2006 and references therein).

The Paf1 complex in yeast is composed of five subunits, Paf1, Rtf1, Cdc73, Ctr9, and Leo1, and is associated with the elongating form of RNA Pol II. The Rtf1 component of Paf1 is required for H2B ubiquitination by Rad6 (Krogan, 2003a; Wood, 2003; Ng, 2003) and for the recruitment of Set1/COMPASS to elongating RNA Pol II. Because Rtf1 is essential for histone monoubiquitination, methylation, and transcriptional control in yeast, the Drosophila homologue dRtf1 was examined to characterize its role in higher eukaryotes. This study used RNAi to reduce dRtf1 expression levels and examine the in vivo effect of dRtf1 reduction on transcription and development in the fly. RNAi knockdown of dRtf1 causes pupal lethality. To demonstrate a role for dRtf1 in gene expression, the effect of dRtf1 RNAi knockdown on heat shock gene expression was tested and it was found that Rtf1 knockdown results in a reduction in heat shock (Hsp70) gene expression. Recently, is has been demonstrated that the Drosophila homologue of Bre1 is required for proper histone H3K4 methylation and is critical for transcription of Notch target genes (Bray, 2005). In this study, it is shown that the dRtf1 component of the Paf1 complex participates in Notch signaling in the wing margins. These studies indicate that transcriptional regulation via the Paf1 complex is highly conserved among eukaryotes (Tenney, 2006).

The yeast Paf1 complex interacts with RNA Pol II and regulates the pattern of histone modifications; deletion of the Rtf1 subunit in yeast has the strongest phenotype on histone H3 modification loss. Analysis of the functional homologue of the Paf1 complex from human cells indicated that this complex includes hCtr9, hPaf1, hLeo1, and hCdc73, and a higher eukaryotic-specific subunit, hSki8 (Zhu, 2005). The Rtf1 subunit does not appear to have a stable interaction with Paf1 complex from either human or Drosophila once purified. However, Rtf1 colocalizes broadly with actively transcribing, phosphorylated RNA Pol II in a pattern very similar to that of Paf1 and CDC73 (Zhu, 2005). These data suggest that Rft1 functions with the Paf1 complex in vivo. These findings regarding the role of Rtf1 in gene expression, Notch signaling, and fly development extend the essential role of this complex in regulating gene expression during development (Tenney, 2006).

Much of the understanding of gene regulation and its role in development and differentiation comes from studies initially performed in yeast and Drosophila. The MLL gene, a frequent partner in chromosome translocations leading to leukemia, exists in a large macromolecular complex, similar to its yeast homologue SET1 in the COMPASS complex. The methylation of histones by yeast COMPASS requires ubiquitination of histone H2B by the Rad6 and Bre1 proteins, and the Paf1 complex is required to activate Rad6 and Bre1 histone ubiquitination activity. This study reports that the Drosophila Rtf1 subunit of the Paf1 complex facilitates Notch signaling, linking histone ubiquitination and methylation to gene activation by the Notch pathway. Previously, it was reported that the Drosophila homologue of Bre1 is also required for expression of Notch target genes and histone H3K4 methylation (Bray, 2005). Work here indicates that Rtf1 contributes to Notch signaling and histone methylation. Therefore, the functional connection among the Paf1 complex, Rad6/Bre1, complex, and the histone H3K4 methylation seen in yeast is conserved in Drosophila. In addition to revealing some of the molecular mechanisms underlying MLL action, these observations predict that the human Paf1 complex will also play a role in Notch signaling and suggest that the Notch pathway may be linked to the pathogenesis of leukemia via the MLL translocations (Tenney, 2006).


GENE STRUCTURE

cDNA clone length - 2522 bp

Bases in 5' UTR - 100

Exons - 4

Bases in 3' UTR - 94

PROTEIN STRUCTURE

Amino Acids - 775

Structural Domains

See InterPro Database IPR004343 Plus-3 for information on Rtf1 structure.


date revised: 9 April 2007 Rtf1: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

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