SUMMARY PARAGRAPH for FKH1
FKH1 is a member of the winged-helix/forkhead (FOX) transcription factor gene family that regulates the expression of the CLB2 cluster of genes during the G2/M phase of the mitotic cell cycle (reviewed in 12 and 13). The CLB2 cluster of genes includes mitotic regulators such as CLB1, CLB2, CDC5 and CDC20 as well as SWI5 and ACE2, transcription factors required for the subsequent temporal wave of cell cycle regulated gene expression in the M/G1 phase interval (14). FHK1 and FKH2 appear to have partially redundant roles in the activation and periodic regulation of genes in the CLB2 cluster based on phenotypes associated with the double deletion strain (2, 15, 3, 1). Strains deleted for both genes also display morphological alterations including defects in cell separation, budding, and the induction of a nutrient-independent pseudohyphal-like growth phenotype that can be suppressed by multicopy CLB2 (2, 15, 3, 1). However, Fkh1p and Fkh2p have distinct functions in the control of G2/M phase transcription and regulation of the cell cycle (2, 15, 3, 1). First, strains deleted for FKH1 alone display enhanced transcription of CLB2 throughout the cell cycle and a slightly elevated rate of progression through the S and G2/M phases of the cell cycle (1). In contrast, FKH2 deletion strains display reduced CLB2 transcription and a reduced rate of progression through the cell cycle (1). Second, Fkh2p (but not Fkh1p) has been identified as a component of Swi-five factor, a factor known to form constitutive ternary complexes with Mcm1p on relevant promoters, as a prerequisite step for the later recruitment of the rate-limiting transcriptional coactivator Ndd1p (15, 3, 16). Third, Fkh1p and Fkh2p display differential promoter occupancy in vivo, and in many cases compete for target promoter occupancy; purified Fkh2p, but not Fkh1p, binds to promoters in a cooperative manner with Mcm1p in vitro (4). Fourth, Fkh1p cooperates with Isw1p to remodel chromatin and repress transcription of CLB2 during G2/M, while Fkh2p cooperates with Isw2p to remodel chromatin and repress CLB2 transcription during G1 phase (17). Finally, Fkh1p and Fkh2p associate with the coding region of active genes where they regulate transcriptional elongation and termination in opposing ways by affecting the phosphorylation status of the C-terminal repeat domain (CTD) of RNA Polymerase II (6).
FKH1 has additional roles in the establishment of a silenced state at HMRa, one of two silent mating type loci, and in the regulation of donor preference during mating type switching. FKH1 was identified as a high-copy-number suppressor of a hypomorphic allele of SIR1, a gene required to establish silencing at the silent mating type loci. FKH1 therefore performs a positive role in silencing at HMRa, whereas FKH2 plays a negative role (1). During mating type switching, information at the MAT locus is replaced by information contained at one of two silent loci, HML or HMR, through a regulated gene conversion event. In MATa strains, HML is the preferred donor, and this preference is dependent upon a cis-acting sequence called the recombination enhancer. FKH1 and the Swi4p/Swi6p containing SCB-binding factor (SBF) independently regulate donor preference through direct interactions with the recombination enhancer, with Fkh1p binding in the G2 phase and SBF binding in the G1 phase of the cell cycle (8). Deletion of FKH1 or mutation of the forkhead binding site in the enhancer reduces usage of the preferred donor and deletion of both FKH1 and SBF results in a nearly complete loss of preference for HML in MATa cells (5).
FKH1 is a member of a conserved forkhead (FOX) family of transcription factors that includes at least 43 members identified in humans, some of which have been implicated in cell cycle regulation (18, 19). Several parallels exist between one of these forkhead factors, FOXM1 (OMIM) and both FKH1 and FKH2. Similar to FKH1 and FKH2, the expression of FOXM1 is induced during the G1/S phase transition (20 and reviewed in 19). FOXM1 regulates the expression of a similar cluster of human genes during G2 and M phase and is required for the proper execution of mitosis and cytokinesis, as well as chromosome stability and the spindle checkpoint (reviewed in 21). The expression of FOXM1 is tightly correlated with cellular proliferative rate, is often elevated in human carcinomas and is actively involved in tumor development (reviewed in 21, 19).
Last updated: 2010-01-28