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Gcn2p regulates a G1/S cell cycle checkpoint in response to DNA damage

ABSTRACT: In Saccharomyces cerevisiae, the Gcn2p kinase controls a gene expression program in response to nutrient deprivation. Upon amino acid deprivation Gcn2p phosphorylates the translation initiation factor 2a subunit (eIF2a). Phosphorylation of eIF2a transiently inhibits translation initiation, and favours selective translation of the GCN4 transcription factor mRNA. High levels of Gcn4p then activate the expression of genes encoding amino acid biosynthesis pathways. Besides nutrient deprivation, Gcn2p can also be activated by other stresses such as DNA damage. Previous studies in our lab suggested that Gcn2p regulated other cellular pathways apart from translation initiation. To gain insights into these new regulatory roles of Gcn2p, we generated a strain called (GCN2c) expressing a constitutively active Gcn2p kinase mutant. In the GCN2c strain, phosphorylation of eIF2a and translation of a GCN4-lacz reporter was constitutively high in the absence of amino acid starvation. We investigated the transcriptional profile of the GCN2c mutant strain by cDNA microarrays. As expected, numerous amino acid biosynthetic genes were upregulated, being dependent of Gcn4p. Most interestingly, expression of genes encoding proteins involved in DNA replication/repair was decreased, suggesting that Gcn2p could regulate cell cycle progression from G1 to S phase. Accordingly, the Gcn2c strain exhibited, i) slow growth, ii) a delayed entry into S phase, and iii) hypersensitivity to hydroxyurea. In addition, MMS treatment induced a G1 checkpoint and a growth defect which was dependent on Gcn2p and Gcn3p. Considering that MMS delays cell cycle progression by generating DNA lesions, the findings suggest that DNA damage induces a G1/S checkpoint by a novel pathway involving the protein kinase Gcn2p. Keywords: mutant analysis Overall design: Four biological replicates were used to assess diferentially expression between wilt type yeast strain and GCN2c overexpressing strain. Differentially expressed genes were identified using one-class significant analysis of microarrays (SAM; Tusher et al, 2004)


SUBMITTER: Jose Ramón Murguía   

PROVIDER: GSE8111 | GEO | 2007-10-22



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Gcn2p regulates a G1/S cell cycle checkpoint in response to DNA damage.

Menacho-Marquez Mauricio M   Perez-Valle Jorge J   Ariño Joaquin J   Gadea Jose J   Murguía Jóse R JR  

Cell cycle (Georgetown, Tex.) 20070702 18

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