SIC1/YLR079W Summary Help

Standard Name SIC1 1
Systematic Name YLR079W
Alias SDB25
Feature Type ORF, Verified
Description Cyclin-dependent kinase inhibitor (CKI); inhibitor of Cdc28-Clb kinase complexes that controls G1/S phase transition, preventing premature S phase and ensuring genomic integrity; phosphorylated by Clb5/6-Cdk1 and Cln1/2-Cdk1 kinase which regulate timing of Sic1p degradation; phosphorylation targets Sic1p for SCF(CDC4)-dependent turnover; functional homolog of mammalian Kip1 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and see Summary Paragraph)
Name Description Substrate/Subunit Inhibitor of Cyclin-dependent protein kinase 1
Chromosomal Location
ChrXII:286820 to 287674 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All SIC1 GO evidence and references
  View Computational GO annotations for SIC1
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 8 genes
Resources
Classical genetics
null
Large-scale survey
null
overexpression
Resources
575 total interaction(s) for 310 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 30
  • Affinity Capture-RNA: 4
  • Affinity Capture-Western: 11
  • Biochemical Activity: 39
  • Co-crystal Structure: 1
  • FRET: 3
  • PCA: 7
  • Protein-peptide: 1
  • Reconstituted Complex: 23
  • Two-hybrid: 8

Genetic Interactions
  • Dosage Growth Defect: 1
  • Dosage Lethality: 8
  • Dosage Rescue: 29
  • Negative Genetic: 222
  • Phenotypic Enhancement: 20
  • Phenotypic Suppression: 23
  • Positive Genetic: 25
  • Synthetic Growth Defect: 66
  • Synthetic Lethality: 42
  • Synthetic Rescue: 12

Resources
Expression Summary
histogram
Resources
Length (a.a.) 284
Molecular Weight (Da) 32,223
Isoelectric Point (pI) 8.94
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXII:286820 to 287674 | ORF Map | GBrowse
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..855 286820..287674 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 SGDIDS000004069
SUMMARY PARAGRAPH for SIC1

SIC1 encodes a cyclin-dependent kinase inhibitor (CKI) that regulates the cell cycle at the G1 to S transition by inhibiting the activity of the cyclin-dependent kinase (CDK) Cdc28p (3 and reviewed in 11 and 12). Sic1p is a potent inhibitor of the cyclin-CDK complexes containing a B-type (Clb) but not a G1 (Cln) cyclin (5, 13). Cells are able to overcome this inhibition and enter S phase by phosphorylating Sic1p and targeting it for degradation via the ubiquitin-mediated proteolysis pathway (reviewed in 14). Cdc28p is able to phosphorylate Sic1p when complexed with a Cln, thus contributing to the alleviation of its own inhibition (15, 16, 7, 17). The phosphorylation state of Sic1p is also regulated by other kinases which include Pho85p (18, 19, 20), casein kinase II (21, 22, 23), Ime2p (24, 25), Hog1p (26) as well as by phosphatases such as Dcr2p (27) and Cdc14p (28, 29). Once Sic1p is phosphorylated on a minimum of six of its nine potential phosphorylation sites, it becomes targeted for degradation (7, 8, 30, 31). Phosphorylated Sic1p is bound by Cdc4p, which is the substrate recognition subunit of the E3 ligase, SCF-Cdc4 (6, 32, 8). In conjunction with the E2 enzyme Cdc34p, SCF-Cdc4 polyubiquitinates Sic1p on N-terminal residues (33, 6, 2, 34, 35, 36, 37). Ubc4p can also serve as an E2 for Sic1p in vitro (34). Once it is ubiquitinated, the polyubiquitin-binding protein Rpn10p targets Sic1p to the 26S proteasome for degradation (38, 39). The proteins Yrb1p and Rad23p are also required for the efficient degradation of Sic1p (40, 41).

Sic1p is an intrinsically disordered protein that can be found in both the cytoplasm and nucleus (42, 43, 30, 44). Subcellular localization of the protein is regulated by carbon source (45). SIC1 is expressed during late mitosis and its transcriptional upregulation is dependent on the transcription factor Swi5p (46, 47, 48). Overexpression of SIC1 results in cells with elongated buds (1) and sic1 null mutants frequently arrest as large-budded cells, have an extended S phase, and inefficiently segregate sister chromatids which leads to genomic instability (1, 49, 50). In addition to being a key cell cycle regulator during G1/S, Sic1p also is involved in regulating exit from mitosis and the process of autophagy (4, 51, 20). Fungal homologs of SIC1 are present in C. albicans and S. pombe (52, 53). Although lacking sequence similarity, Sic1p is functionally and structurally related to the mammalian Cdk inhibitor Kip1/p27 (43, 9).

Last updated: 2011-02-07 Contact SGD

References cited on this page View Complete Literature Guide for SIC1
1) Nugroho TT and Mendenhall MD  (1994) An inhibitor of yeast cyclin-dependent protein kinase plays an important role in ensuring the genomic integrity of daughter cells. Mol Cell Biol 14(5):3320-8
2) Feldman RM, et al.  (1997) A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91(2):221-30
3) Schwob E, et al.  (1994) The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell 79(2):233-44
4) Donovan JD, et al.  (1994) P40SDB25, a putative CDK inhibitor, has a role in the M/G1 transition in Saccharomyces cerevisiae. Genes Dev 8(14):1640-53
5) Mendenhall MD  (1993) An inhibitor of p34CDC28 protein kinase activity from Saccharomyces cerevisiae. Science 259(5092):216-9
6) Skowyra D, et al.  (1997) F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91(2):209-19
7) Verma R, et al.  (1997) Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. Science 278(5337):455-60
8) Nash P, et al.  (2001) Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414(6863):514-21
9) Barberis M, et al.  (2005) The yeast cyclin-dependent kinase inhibitor Sic1 and mammalian p27Kip1 are functional homologues with a structurally conserved inhibitory domain. Biochem J 387(Pt 3):639-47
10) Yang X, et al.  (2013) Design principles of the yeast g1/s switch. PLoS Biol 11(10):e1001673
11) Enserink JM and Kolodner RD  (2010) An overview of Cdk1-controlled targets and processes. Cell Div 5():11
12) Mendenhall MD, et al.  (1995) The Cdc28 inhibitor p40SIC1. Prog Cell Cycle Res 1():173-85
13) Weinreich M, et al.  (2001) Binding of cyclin-dependent kinases to ORC and Cdc6p regulates the chromosome replication cycle. Proc Natl Acad Sci U S A 98(20):11211-7
14) Sheaff RJ and Roberts JM  (1996) End of the line: proteolytic degradation of cyclin-dependent kinase inhibitors. Chem Biol 3(11):869-73
15) Wittenberg C and Reed SI  (1988) Control of the yeast cell cycle is associated with assembly/disassembly of the Cdc28 protein kinase complex. Cell 54(7):1061-72
16) Mendenhall MD, et al.  (1987) Dual regulation of the yeast CDC28-p40 protein kinase complex: cell cycle, pheromone, and nutrient limitation effects. Cell 50(6):927-35
17) Schneider BL, et al.  (1996) Linkage of replication to start by the Cdk inhibitor Sic1. Science 272(5261):560-2
18) Wysocki R, et al.  (2006) CDK Pho85 targets CDK inhibitor Sic1 to relieve yeast G1 checkpoint arrest after DNA damage. Nat Struct Mol Biol 13(10):908-14
19) Nishizawa M, et al.  (1998) Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation. Mol Biol Cell 9(9):2393-405
20) Yang Z, et al.  (2010) Positive or negative roles of different cyclin-dependent kinase Pho85-cyclin complexes orchestrate induction of autophagy in Saccharomyces cerevisiae. Mol Cell 38(2):250-64
21) Coccetti P, et al.  (2006) Sic1 is phosphorylated by CK2 on Ser201 in budding yeast cells. Biochem Biophys Res Commun 346(3):786-93
22) Barberis M, et al.  (2005) CK2 regulates in vitro the activity of the yeast cyclin-dependent kinase inhibitor Sic1. Biochem Biophys Res Commun 336(4):1040-8
23) Coccetti P, et al.  (2004) Mutations of the CK2 phosphorylation site of Sic1 affect cell size and S-Cdk kinase activity in Saccharomyces cerevisiae. Mol Microbiol 51(2):447-60
24) Sedgwick C, et al.  (2006) Saccharomyces cerevisiae Ime2 phosphorylates Sic1 at multiple PXS/T sites but is insufficient to trigger Sic1 degradation. Biochem J 399(1):151-60
25) Dirick L, et al.  (1998) Regulation of meiotic S phase by Ime2 and a Clb5,6-associated kinase in Saccharomyces cerevisiae. Science 281(5384):1854-7
26) Escote X, et al.  (2004) Hog1 mediates cell-cycle arrest in G1 phase by the dual targeting of Sic1. Nat Cell Biol 6(10):997-1002
27) Pathak R, et al.  (2007) The Dcr2p phosphatase destabilizes Sic1p in Saccharomyces cerevisiae. Biochem Biophys Res Commun 361(3):700-4
28) Visintin R, et al.  (1998) The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol Cell 2(6):709-18
29) Wasch R and Cross FR  (2002) APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit. Nature 418(6897):556-62
30) Mittag T, et al.  (2010) Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase. Structure 18(4):494-506
31) Borg M, et al.  (2007) Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc Natl Acad Sci U S A 104(23):9650-5
32) Deshaies RJ and Ferrell JE Jr  (2001) Multisite phosphorylation and the countdown to S phase. Cell 107(7):819-22
33) Verma R, et al.  (1997) SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. Mol Biol Cell 8(8):1427-37
34) Kus BM, et al.  (2004) Functional interaction of 13 yeast SCF complexes with a set of yeast E2 enzymes in vitro. Proteins 54(3):455-67
35) Petroski MD and Deshaies RJ  (2005) Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34. Cell 123(6):1107-20
36) Sadowski M, et al.  (2010) Molecular basis for lysine specificity in the yeast ubiquitin-conjugating enzyme Cdc34. Mol Cell Biol 30(10):2316-29
37) Petroski MD and Deshaies RJ  (2003) Context of multiubiquitin chain attachment influences the rate of Sic1 degradation. Mol Cell 11(6):1435-44
38) Mayor T, et al.  (2005) Analysis of polyubiquitin conjugates reveals that the Rpn10 substrate receptor contributes to the turnover of multiple proteasome targets. Mol Cell Proteomics 4(6):741-51
39) Verma R, et al.  (2001) Selective degradation of ubiquitinated Sic1 by purified 26S proteasome yields active S phase cyclin-Cdk. Mol Cell 8(2):439-48
40) Baumer M, et al.  (2000) Yeast Ran-binding protein Yrb1p is required for efficient proteolysis of cell cycle regulatory proteins Pds1p and Sic1p. J Biol Chem 275(49):38929-37
41) Verma R, et al.  (2004) Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell 118(1):99-110
42) Mittag T, et al.  (2008) Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc Natl Acad Sci U S A 105(46):17772-7
43) Brocca S, et al.  (2009) Order propensity of an intrinsically disordered protein, the cyclin-dependent-kinase inhibitor Sic1. Proteins 76(3):731-46
44) Edgington NP and Futcher B  (2001) Relationship between the function and the location of G1 cyclins in S. cerevisiae. J Cell Sci 114(Pt 24):4599-611
45) Rossi RL, et al.  (2005) Subcellular localization of the cyclin dependent kinase inhibitor Sic1 is modulated by the carbon source in budding yeast. Cell Cycle 4(12):1798-807
46) Knapp D, et al.  (1996) The transcription factor Swi5 regulates expression of the cyclin kinase inhibitor p40SIC1. Mol Cell Biol 16(10):5701-7
47) Toyn JH, et al.  (1997) The Swi5 transcription factor of Saccharomyces cerevisiae has a role in exit from mitosis through induction of the cdk-inhibitor Sic1 in telophase. Genetics 145(1):85-96
48) Kishi T, et al.  (2008) A refined two-hybrid system reveals that SCFCdc4-dependent degradation of Swi5 contributes to the regulatory mechanism of S-phase entry. Proc Natl Acad Sci U S A 105(38):14497-502
49) Lengronne A and Schwob E  (2002) The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1). Mol Cell 9(5):1067-78
50) Ross KE and Cohen-Fix O  (2003) The role of Cdh1p in maintaining genomic stability in budding yeast. Genetics 165(2):489-503
51) Calzada A, et al.  (2001) Cdc6 cooperates with Sic1 and Hct1 to inactivate mitotic cyclin-dependent kinases. Nature 412(6844):355-8
52) Atir-Lande A, et al.  (2005) Role for the SCFCDC4 ubiquitin ligase in Candida albicans morphogenesis. Mol Biol Cell 16(6):2772-85
53) Sanchez-Diaz A, et al.  (1998) The Cdk inhibitors p25rum1 and p40SIC1 are functional homologues that play similar roles in the regulation of the cell cycle in fission and budding yeast. J Cell Sci 111 ( Pt 6)():843-51