Abstract
Cip1, a newly identified yeast analog of p21, is a Cln3-CDK inhibitor that negatively regulates cell-cycle START. However, its function remains poorly understood. In this study, we found that deletion of CLN3 did not result in bypass of G1-phase arrest caused by Cip1 overexpression. Cip1 depletion in cln3-null mutants significantly advanced the timing of Cln2 expression, supporting the idea that Cip1 represses START in a Cln3-independent manner. We set to search for novel Cip1 interacting proteins and found that Ccr4, a known START regulator, and its associated factor Caf120, interact with Cip1. Ccr4-Caf120 acts redundantly with Cdk1-Cln3 to inhibit Whi5-mediated regulation of START. This interaction was conserved between human Ccr4 and p21. In addition, deletion of WHI5 robustly suppressed G1-phase arrest caused by Cip1 overexpression. We conclude that Cip1 negatively regulates START by acting as a dual repressor of Ccr4 in parallel with Cln3.
Highlights
In budding yeast, as well as in mammals, cell proliferation is primarily regulated at the G1/Sphase transition in response to a variety of environmental and internal signals (Bertoli et al, 2013)
START is promoted through activation of the cell size-dependent regulator Cln3-Cdk1, which relocalizes to the nucleus upon activation and phosphorylates the retinoblastoma (Rb) ortholog Whi5 (Wittenberg and Reed, 2005; Palumbo et al, 2016)
SBF is responsible for expression of late G1 genes, including cyclins encoded by CLN1 and CLN2, resulting in cell-cycle entry
Summary
As well as in mammals, cell proliferation is primarily regulated at the G1/Sphase transition in response to a variety of environmental and internal signals (Bertoli et al, 2013). SBF is responsible for expression of late G1 genes, including cyclins encoded by CLN1 and CLN2, resulting in cell-cycle entry. This mechanism is analogous to the regulation of E2F transcription by the tumor suppressor Rb, which constitutes a key barrier to carcinogenesis in human cells (Bruin et al, 2004; Costanzo et al, 2004; Cooper, 2006). Dual Repressive Function by Cip unwanted cell division at the G1/S transition (Georgakilas et al, 2017) This strategy for regulating CDK activity is conserved from yeast to human, but previously no p21 or p53 homolog had been identified in yeast. Our results demonstrate that Cip blocks the cell cycle at START by acting as a dual repressor of Ccr4Caf120 and Cdk1-Cln
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