Disease relevance of SIC1

• In addition, comparison of the different inhibitory patterns obtained using histone H1 or GST (glutathione S-transferase)-pRb (retinoblastoma protein) fusion protein as substrate (the latter of which recognizes both the docking site and the catalytic site of Cdk2-cyclin A) offers interesting suggestions for the inhibitory mechanism of Sic1 [1].

High impact information on SIC1

• Biochemical reconstitution with purified Sic1, a prototype substrate of the Cdc34/SCF ubiquitin ligase, suggests that substrate degradation is essential for triggering the ATP hydrolysis-dependent dissociation and disassembly of the 19S and that this mechanism leads to release of degradation products [2].
• By using a F72VCdc34 mutant with increased affinity for the RING domain, we demonstrate that release of ubiquitin-charged Cdc34-S - Ub from the RING is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1 [3].
• The low affinity of each CPD motif in Sic1 reflects structural discordance with one or more elements of the Cdc4 binding site [4].
• Viability of hct1 mutants depends on SIC1 [5].
• Phosphorylated Sic1p substrate is specifically targeted for ubiquitination by binding to a Cdc4p/Skp1p subcomplex [6].

Biological context of SIC1

• Our data suggest that cell cycle-regulated nuclear accumulation of Swi5 is responsible for the burst of SIC1 transcription at the end of anaphase [7].
• Cell cycle-regulated proteolysis seems largely responsible for this pattern, but transcriptional control could also contribute; SIC1 RNA accumulates to high levels as cells exit M phase [7].
• Deletion of SIC1 allows these mutants to replicate. p40SIC1 disappears at the G1/S transition and reappears only after nuclear division [7].
• Traversal from G1 to S-phase in cycling cells of budding yeast is dependent on the destruction of the S-phase cyclin/CDK inhibitor SIC1 [8].
• We have shown previously that the Swi5 transcription factor regulates the expression of the SIC1 Cdk inhibitor in late mitosis [9].

Anatomical context of SIC1

• RAD9, which is necessary for the DNA damage checkpoint, is required for the preanaphase arrest of sid2-1 sic1 Delta cells [10].

Associations of SIC1 with chemical compounds

• The effects of glucose on Sic1p levels and DNA replication required Grr1p, a component of the SCF(Grr1p) ubiquitin ligase [11].
• Here we show by direct mass spectrometry analysis that Sic1, but not a mutant protein whose CK2 phospho-acceptor site has been mutated to alanine, Sic1S201A, is actually phosphorylated in vitro by CK2 on Serine 201 [12].

Physical interactions of SIC1

• The complementary C-terminal segment of SIC1 binds to the S-phase cyclin CLB5, indicating a modular structure for SIC1 [8].
• We show that fusion of the Cln2 domain to a stabilized form of the cyclin-dependent kinase inhibitor Sic1 (Delta N-Sic1), a substrate of SCF(Cdc4), results in degradation in a phosphorylation-dependent manner [13].
• During late mitosis, Cdc6 is present at levels comparable with Sic1 and binds specifically to the mitotic cyclin Clb2 [14].

Enzymatic interactions of SIC1

• Cdc4 assembled with Skp1 functions as the receptor that selectively binds phosphorylated Sic1 [15].
• Pho85 and other G1 Cdks appear to phosphorylate Sic1 at different sites in vivo [16].
• We found that Ime2 phosphorylates Sic1 at multiple sites in vitro [17].

Regulatory relationships of SIC1

• Exit from mitosis in yeast involves accumulation of the cyclin kinase inhibitor Sic1 as well as cyclin proteolysis mediated by APC/C bound by the activating subunit Cdh1/Hct1 (APC(Cdh1)) [18].
• Sic1p is negatively regulated by Ime2p kinase, and several observations indicate that glucose inhibits meiotic DNA replication through SCF(Grr1p)-mediated destruction of this kinase [11].
• The highly conserved protein phosphatase Cdc14 promotes both Clb degradation and Sic1 accumulation [19].
• Here we show that Hog1 regulates cell cycle progression at the G1 phase by a dual mechanism that involves downregulation of cyclin expression and direct targeting of the CDK-inhibitor protein Sic1 [20].
• The CKI Sic1 controls the timing of DNA replication by inhibiting Clb-Cdc28 kinase [21].

Other interactions of SIC1

• The fkh1 fkh2 mutant also displays aberrant regulation of the 'SIC1' cluster, whose member genes are expressed in the M-G1 interval and are involved in mitotic exit [22].
• In mitosis, Cdc28p controls its own S-phase-promoting activity by signaling the destruction of its inhibitor, Sic1p [23].
• In meiosis, Sic1p destruction is signaled by the meiosis-specific Ime2p protein kinase [23].
• While the G(1)/S block in both cdc4-12 and cdc4Delta mutants is abolished by the deletion of the SIC1 gene (causing the mutants to be arrested predominantly in G(2)/M), the preanaphase arrest in the cdc4-12 mutant is relieved by the deletion of PDS1 [24].
• Consistent with Cak1p's role in activating Ime2p, cells lacking Cak1p are deficient in degrading Sic1p [23].

Analytical, diagnostic and therapeutic context of SIC1

• By sequence analysis we found an amino acid stretch centred on Serine201 matching a stringent CK2 consensus site within the C-terminal, inhibitory domain of Sic1 [12].
• Here we present new evidence, by using specific anti-P-Ser201 antibodies and 2-D gel electrophoresis coupled to MALDI mass spectrometry analysis, that Sic1 is phosphorylated in vivo on Ser201 shortly after its de novo synthesis, during late anaphase in glucose-grown cells [25].

References