Filamentous Differentiation of S. cerevisiae
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Filamentous Differentiation of S. cerevisiae

Unicellular S. cerevisiae (Saccharomyces cerevisiae) undergoes developmental switches between two differentiation states in response to environmental cues. Under stress conditions, diploid S. cerevisiae cells switch from the yeast form (growth as single oval cells) to the filamentous or pseudohyphae form (growth as elongated cell chains that retain physical attachment between the mother and daughter cells). Filamentous differentiation of S. cerevisiae is a potential model system for study of eukaryotic differentiation. Slowed DNA synthesis induces filamentous differentiation in yeast and it involves the conserved cell cycle regulators Swe1 (Mitosis Inhibitor Protein Kinase-Swe1), Clb2 and CDC28 (Cell Division Control Protein-28) (Ref.1). DNA integrity checkpoints are conserved signaling pathways that are activated by DNA damage or replication blocks to delay cell cycle progression until DNA repair or replication is finished. At the heart of the checkpoints are highly conserved proteins that are required for cell cycle arrest; Mec1 and Rad53 (or Mec2). In S. cerevisiae, Rad53 is activated by DNA damage in a distinct Rad9 (DNA Repair Protein-Rad9)-dependent checkpoint that causes mitotic arrest in G1 and G2 phases. The checkpoint proteins have more widespread roles like regulation of dNTP synthesis that are independent of cell cycle. The checkpoint proteins Mec1 and Rad53 have one additional function; to initiate filamentous differentiation in S. cerevisiae in response to slowed DNA synthesis (Ref.1 & 2).

DNA synthesis involves multiple steps, and inhibitors or inhibitory conditions block or slow DNA synthesis at distinct steps. Hydroxyurea blocks DNA synthesis by inhibiting Ribonucleotide Reductase, RNR1/RIR1 (Ribonucleoside-Diphosphate Reductase Large Chain-1) that catalyzes dNTP synthesis (Ref.1). Dun1 encodes a downstream kinase that enhances RNR1/RIR1 gene expression and the Ribonucleotide Reductase activity, both at transcriptional and post-translational levels, by opposing Crt1/Rfx1 (Rfx-Like DNA-Binding Protein-Rfx1) and Sml1 (Ribonucleotide Reductase Inhibitor Protein-Sml1), respectively in Mec1-Rad53 mediated responses to DNA replication block or DNA damage. Cellular uptake and intracellular phosphorylation of the nucleotide Ara-CTP (Cytarabine-5’-Triphosphate), an analog of dCTP (a natural substrate of DNA polymerases) blocks DNA fragment synthesis by inhibiting DNA polymerases through competition with dCTP. DNA-alkylating agent like MMS (Methyl Methansulfonate) blocks DNA synthesis by stalling DNA replication forks. DNA Ligases, ligates newly synthesized DNA fragments to complete DNA synthesis. However changes in temperature blocks DNA Ligase activity during DNA synthesis. Such conditions slow DNA synthesis and induce filamentous differentiation in yeast (Ref.2 & 3).

The requirement of Swe1 and Clb2 in order to slow down DNA synthesis and induce filamentous differentiation is regarded as the core status for Swe1-Clb2-CDC28 in the mechanism of filamentous differentiation. Swe1 phosphorylates CDC28 to inhibit the Clb2 and CDC28 activity. As CDC28 regulates cell cycle progression, inhibition of the mitotic Cyclin-dependent Kinase Clb2 and CDC28 activity is a pivotal event leading to filamentous differentiation since when cells start to differentiate, they stop proliferating. Filamentous differentiation of S. cerevisiae is regarded as a potential model for mammalian cell differentiation. Slowed DNA synthesis induces yeast filamentous differentiation in yeast through conserved cell cycle regulators of Swe1 and CDC28 (Ref.3). Experiments on induction of yeast differentiation by the mammalian differentiation stimuli through the conserved cell cycle regulator proteins strongly show that the core mechanism (Swe1-Clb2-CDC28) for cell differentiation might be evolutionarily conserved in mammals and yeast. More significantly, slowed DNA synthesis also induces differentiation in mammalian cancer cells, and such stimulus conservation indicates that the core mechanism for yeast filamentous differentiation is conserved in mammalian differentiation (Ref.2 & 3).