SUMMARY PARAGRAPH for FHL1
Originally isolated as a suppressor of an RNA polymerase III mutation and independently as a supressor of a splicing mutation, FHL1 encodes a protein that is involved in regulation of the expression of ribosomal protein (RP) genes by RNA polymerase II (1, 2, 10, and reviewed in 8). Fhl1p has sequence similarity to the forkhead (FH), or "winged helix", domain generally considered to be a DNA binding domain (11, 1). However in vitro studies testing for direct DNA binding by Fhl1p have produced inconsistent results (5, 6, 7), and the FH domain can be deleted with almost no effect on cells (5). In constrast, deletion of the forkhead-associated (FHA) domain, which is involved in binding to phosphorylated threonine residues within proteins (12) and required for the interaction of Fhl1p with either Ifh1p or Crf1p (4), is nearly as deleterious as deletion of the entire FHL1 gene (5). Null mutations of FHL1 result in a severely reduced growth rate with cells having only 20% the normal amount of RNA and able to synthesize ribosomes at 5-10% the rate of wild-type cells (1, 5).
RP gene transcription is coordinated with that of rDNA transcription and is regulated in response to stress and growth conditions through a complex mechanism that involves Fhl1p, the coactivator Ifh1p, the corepressor Crf1p, and the TOR pathway (4). Fhl1p localizes to promoters of RP genes, where it can recruit either the activator protein Ifh1p or the repressor protein Crf1p (4, 11). Both Fhl1p and Ifh1p are localized to the nucleus all the time, but the localization of the repressor Crf1p is regulated by its phosphorylation state via the TOR pathway (4). Fhl1p localization to RP gene promoters and RP gene expression are dependent on Rap1p and Hmo1p (13, 14), however the phenotypes of both hmo1 and fhl1 nulls suggest that there is an additional pathway that regulates RP gene transcription (5, 14). Fhl1p is also loosely associated with the CURI complex, which is thought to repress transcription of ribosomal protein genes by sequestering the coactivator Ifh1p (15). Both the CURI complex and Hmo1p, which is required for rDNA transcription by RNA polymerase I, are thought to be involved in coordinate regulation of rDNA transcription and RP gene transcription to control production of ribosomes in response to growth conditions (reviewed in 8).
Founded by the forkhead homeotic gene of the fruit fly D. melanogaster, the forkhead family of proteins (FOX) contain the characteristic Fork Head (FH) domain and are widespread in eukaryotes, found throughout animals and fungi (16). The forkhead domains of animal and fungal sequences can be classified into a number of orthologous groups, with the members of the fungal groups being more similar to each other than to forkhead proteins from animals (16). Of the three groups found in fungi, S. cerevisiae has members in two of the groups: FKH1 and FKH2 in the Fox1 group and FHL1 in the Fox3 group (16). Many forkhead proteins have a second domain referred to as the Fork Head Associated (FHA) domain, though this domain is also found in other protein families and in plants and prokaryotes (12). The S. cerevisiae Fhl1 protein is similar to the FHA-domain containing proteins Fhl1 from S. pombe (17) and NtFHA1 from tobacco which can complement a fhl1 null mutation (18).
Last updated: 2010-02-12