FKH2/YNL068C Summary Help

Standard Name FKH2 1
Systematic Name YNL068C
Feature Type ORF, Verified
Description Forkhead family transcription factor; plays a major role in the expression of G2/M phase genes; positively regulates transcriptional elongation; facilitates clustering and activation of early-firing replication origins; negative role in chromatin silencing at HML and HMR; substrate of the Cdc28p/Clb5p kinase; relocalizes to the cytosol in response to hypoxia; FKH2 has a paralog, FKH1, that arose from the whole genome duplication (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and see Summary Paragraph)
Name Description ForK head Homolog 1
Chromosomal Location
ChrXIV:498289 to 495701 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Gbrowse
Gene Ontology Annotations All FKH2 GO evidence and references
  View Computational GO annotations for FKH2
Molecular Function
Manually curated
High-throughput
Biological Process
Manually curated
Cellular Component
Manually curated
Targets 190 genes
Regulators 2 genes
Resources
Classical genetics
null
overexpression
Large-scale survey
null
overexpression
Resources
182 total interaction(s) for 132 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 7
  • Affinity Capture-RNA: 2
  • Affinity Capture-Western: 10
  • Biochemical Activity: 4
  • PCA: 1
  • Protein-RNA: 1
  • Reconstituted Complex: 8

Genetic Interactions
  • Dosage Growth Defect: 11
  • Dosage Rescue: 2
  • Negative Genetic: 94
  • Phenotypic Enhancement: 6
  • Phenotypic Suppression: 3
  • Positive Genetic: 22
  • Synthetic Growth Defect: 7
  • Synthetic Lethality: 3
  • Synthetic Rescue: 1

Resources
Expression Summary
histogram
Resources
Length (a.a.) 862
Molecular Weight (Da) 94,374
Isoelectric Point (pI) 10.13
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXIV:498289 to 495701 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..2589 498289..495701 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000005012
SUMMARY PARAGRAPH for FKH2

FKH2 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 11 and 12). The CLB2 cluster 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 (13). Promoter sequences responsible for restricting transcription of genes in this cluster to the late S, G2 and M phases were first identified upstream of SWI5 and CLB2 (14, 15). These cell cycle regulated upstream activating sequences (UAS) contain binding sites for the MADS-box protein Mcm1p and for SWI five factor (SFF), an activity known to be involved in the formation of ternary complexes at these promoters in the presence of Mcm1p (14, 15). Fkh2p was subsequently identified as a component of SFF (16, 3). Inclusion of Fkh2p in the complex is facilitated by DNA bending induced by Mcm1p (16, 3, 17). The rate-limiting transcriptional coactivator Ndd1p is subsequently recruited to the chromatin of G2/M regulated promoters through interactions with Fkh2p in a manner that is dependent on both the phosphorylation of Ndd1p by the Cdc28p-Clb2p kinase complex and the phosphorylation of Fkh2p by one or more complexes containing Cdc28p with a B-type cyclin (Clb2p or Clb5p) (see below) (18, 19, 20, 7). Fkh2p is also required for the recruitment of the Cdc5p polo-like kinase, nucleating the formation of a Fkh2p-Ndd1p-Cdc5p complex on CLB2 cluster promoters and leading to the phosphorylation of Ndd1p by Cdc5p, an event required for the proper temporal activation of CLB2 cluster genes during G2/M (21). In contrast, Fkh2p can also cooperate with Isw2p, a chromatin-remodeling ATPase, to remodel chromatin which may be important for repression of CLB2 transcription during the G1 phase (22).

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, 16, 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, 16, 3, 1). However, Fkh1p and Fkh2p have distinct functions in the control of G2/M phase transcription and regulation of the cell cycle (2, 16, 3, 1). First, as discussed above, Fkh2p (but not Fkh1p) is a component of SFF, an activity that forms ternary complexes at relevant promoters in the presence of Mcm1p (16, 3). Second, strains deleted for FKH2 display reduced CLB2 transcription and a reduced rate of progression through the cell cycle while strains deleted for FKH1 display enhanced transcription of CLB2 and a slightly elevated rate of progression through the S and G2/M phases of the cell cycle (1). 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, Fkh2p cooperates with Isw2p to remodel chromatin and repress transcription of CLB2 during G1 phase, while Fkh1p cooperates with Isw1p to remodel chromatin and repress CLB2 transcription during G2/M phase (22). Finally, Fkh1p and Fkh2p associate with the coding regions 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 (5).

FKH2 is subject to both transcriptional and post-translational regulation. FKH2 is periodically expressed in late S-phase through the actions of another forkhead family transcription factor, Hcm1p (23). Post-translationally Fkh2p is subject to cell cycle-dependent C-terminal phosphorylation by Cdc28p-Clb5p complexes, although Cdc28p-Clb2p complexes are also capable of phosphorylating the same residues (7). Phosphorylation of the C-terminal region of Fkh2p facilitates the recruitment of the rate-limiting transcriptional coactivator Ndd1p to CLB2 cluster promoters (7).

FKH2 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 (24, 25). 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 (23 and reviewed in 25). FOXM1 regulates the expression of a similar cluster of genes during G2 and M phases and is required for the proper execution of mitosis, cytokinesis, as well as chromosome stability and the spindle checkpoint (reviewed in 26). 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 26, 25).

Last updated: 2010-01-28 Contact SGD

References cited on this page View Complete Literature Guide for FKH2
1) Hollenhorst PC, et al.  (2000) Forkhead genes in transcriptional silencing, cell morphology and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae. Genetics 154(4):1533-48
2) Zhu G, et al.  (2000) Two yeast forkhead genes regulate the cell cycle and pseudohyphal growth. Nature 406(6791):90-4
3) Kumar R, et al.  (2000) Forkhead transcription factors, Fkh1p and Fkh2p, collaborate with Mcm1p to control transcription required for M-phase. Curr Biol 10(15):896-906
4) Hollenhorst PC, et al.  (2001) Mechanisms controlling differential promoter-occupancy by the yeast forkhead proteins Fkh1p and Fkh2p: implications for regulating the cell cycle and differentiation. Genes Dev 15(18):2445-56
5) Morillon A, et al.  (2003) Regulation of elongating RNA polymerase II by forkhead transcription factors in yeast. Science 300(5618):492-5
6) Ubersax JA, et al.  (2003) Targets of the cyclin-dependent kinase Cdk1. Nature 425(6960):859-64
7) Pic-Taylor A, et al.  (2004) Regulation of cell cycle-specific gene expression through cyclin-dependent kinase-mediated phosphorylation of the forkhead transcription factor Fkh2p. Mol Cell Biol 24(22):10036-46
8) Byrne KP and Wolfe KH  (2005) The Yeast Gene Order Browser: combining curated homology and syntenic context reveals gene fate in polyploid species. Genome Res 15(10):1456-61
9) Knott SR, et al.  (2012) Forkhead Transcription Factors Establish Origin Timing and Long-Range Clustering in S. cerevisiae. Cell 148(1-2):99-111
10) Ghosh Dastidar R, et al.  (2012) The nuclear localization of SWI/SNF proteins is subjected to oxygen regulation. Cell Biosci 2(1):30
11) Jorgensen P and Tyers M  (2000) The fork'ed path to mitosis. Genome Biol 1(3):REVIEWS1022
12) Bahler J  (2005) Cell-cycle control of gene expression in budding and fission yeast. Annu Rev Genet 39:69-94
13) Spellman PT, et al.  (1998) Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol Biol Cell 9(12):3273-97
14) Maher M, et al.  (1995) Cell cycle-regulated transcription of the CLB2 gene is dependent on Mcm1 and a ternary complex factor. Mol Cell Biol 15(6):3129-37
15) Lydall D, et al.  (1991) A new role for MCM1 in yeast: cell cycle regulation of SW15 transcription. Genes Dev 5(12B):2405-19
16) Pic A, et al.  (2000) The forkhead protein Fkh2 is a component of the yeast cell cycle transcription factor SFF. EMBO J 19(14):3750-61
17) Lim FL, et al.  (2003) Mcm1p-induced DNA bending regulates the formation of ternary transcription factor complexes. Mol Cell Biol 23(2):450-61
18) Koranda M, et al.  (2000) Forkhead-like transcription factors recruit Ndd1 to the chromatin of G2/M-specific promoters. Nature 406(6791):94-8
19) Reynolds D, et al.  (2003) Recruitment of Thr 319-phosphorylated Ndd1p to the FHA domain of Fkh2p requires Clb kinase activity: a mechanism for CLB cluster gene activation. Genes Dev 17(14):1789-802
20) Darieva Z, et al.  (2003) Cell cycle-regulated transcription through the FHA domain of Fkh2p and the coactivator Ndd1p. Curr Biol 13(19):1740-5
21) Darieva Z, et al.  (2006) Polo kinase controls cell-cycle-dependent transcription by targeting a coactivator protein. Nature 444(7118):494-8
22) Sherriff JA, et al.  (2007) The Isw2 chromatin-remodeling ATPase cooperates with the Fkh2 transcription factor to repress transcription of the B-type cyclin gene CLB2. Mol Cell Biol 27(8):2848-60
23) Pramila T, et al.  (2006) The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle. Genes Dev 20(16):2266-78
24) Katoh M and Katoh M  (2004) Human FOX gene family (Review). Int J Oncol 25(5):1495-500
25) Carlsson P and Mahlapuu M  (2002) Forkhead transcription factors: key players in development and metabolism. Dev Biol 250(1):1-23
26) Laoukili J, et al.  (2007) FoxM1: At the crossroads of ageing and cancer. Biochim Biophys Acta 1775(1):92-102
27) Harbison CT, et al.  (2004) Transcriptional regulatory code of a eukaryotic genome. Nature 431(7004):99-104
28) Badis G, et al.  (2008) A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targeting nucleosome exclusion at promoters. Mol Cell 32(6):878-87
29) Zhu C, et al.  (2009) High-resolution DNA-binding specificity analysis of yeast transcription factors. Genome Res 19(4):556-66