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Mol Biol Cell

Title:		Functional overlap among distinct G1/S inhibitory pathways allows robust G1 arrest by yeast mating pheromones
Author(s):		Pope PA; Pryciak PM;
Address:		"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605"
Journal Title:		Mol Biol Cell
Year:		2013
Volume:		20131002
Issue:		23
Page Number:		3675 - 3688
DOI:		10.1091/mbc.E13-07-0373
ISSN/ISBN:		1939-4586 (Electronic) 1059-1524 (Print) 1059-1524 (Linking)
Abstract:		"In budding yeast, mating pheromones arrest the cell cycle in G1 phase via a pheromone-activated Cdk-inhibitor (CKI) protein, Far1. Alternate pathways must also exist, however, because deleting the cyclin CLN2 restores pheromone arrest to far1 cells. Here we probe whether these alternate pathways require the G1/S transcriptional repressors Whi5 and Stb1 or the CKI protein Sic1, whose metazoan analogues (Rb or p27) antagonize cell cycle entry. Removing Whi5 and Stb1 allows partial escape from G1 arrest in far1 cln2 cells, along with partial derepression of G1/S genes, which implies a repressor-independent route for inhibiting G1/S transcription. This route likely involves pheromone-induced degradation of Tec1, a transcriptional activator of the cyclin CLN1, because Tec1 stabilization also causes partial G1 escape in far1 cln2 cells, and this is additive with Whi5/Stb1 removal. Deleting SIC1 alone strongly disrupts Far1-independent G1 arrest, revealing that inhibition of B-type cyclin-Cdk activity can empower weak arrest pathways. Of interest, although far1 cln2 sic1 cells escaped G1 arrest, they lost viability during pheromone exposure, indicating that G1 exit is deleterious if the arrest signal remains active. Overall our findings illustrate how multiple distinct G1/S-braking mechanisms help to prevent premature cell cycle commitment and ensure a robust signal-induced G1 arrest"
Keywords:		"G1 Phase Cell Cycle Checkpoints/*drug effects/genetics Gene Expression Regulation, Fungal/drug effects *Genes, Mating Type, Fungal Microbial Viability/drug effects/genetics Models, Biological Pheromones/*pharmacology RNA, Messenger/genetics/metabolism Rep;"
Notes:		"MedlinePope, Patricia A Pryciak, Peter M eng R01 GM057769/GM/NIGMS NIH HHS/ GM57769/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural 2013/10/04 Mol Biol Cell. 2013 Dec; 24(23):3675-88. doi: 10.1091/mbc.E13-07-0373. Epub 2013 Oct 2"