Transcriptional regulation of meiosis in budding yeast

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esulting in the transient transcription of IME1 and EMG. According to this model, in cells deleted for IME2, the continuous presence of Ime1 leads to the non-transient expression of IME1 and EMG (Mitchell et al., 1990; Yoshida et al., 1990). ii. In the meiotic cycle, upon completion of premeiotic DNA replication and the presence of Ime2, two subunits of the DNA polymerase αprimase complex, Pol1 and Pol12, are degraded (Foiani et al., 1996). iii. The level of the Clb/Cdc28 inhibitor, Sic1, is reduced under meiotic conditions, a process regulated by Ime2 (Dirick et al., 1998). iv. When Ime2 is ectopically expressed in the cell cycle it phosphorylates Cdh1, an event causing dissociation of Cdh1 from APC (anaphase promoting complex – the ubiquitin ligase required for proteolysis of specific substrates), and consequently stabilization of its substrates, such as Clb2 and Cdc5 (Bolte et al., 2002). It is not known if Ime2 phosphorylate Cdh1 in the meiotic cycle, and what are the consequences of this event for entry into the meiotic divisions. v. In the meiotic cycle Ime2 is required to limit premeiotic DNA replication and nuclear division to one and two rounds, respectively (Foiani et al., 1996). It is assumed that this phenomenon results from stabilization of specific proteins or regulators of DNA replication and nuclear divisions. The availability and function of Ime2 is regulated in several levels: Transcriptional regulation: The transcription of IME2 is silent in vegetative growth conditions by the binding and activity of the Ume6/Sin3/Rpd3 and Ume6/Isw2 complexes to the URS1 element present in its promoter. Under meiotic condition, recruitment of Ime1 by Ume6 promotes the transcription of Ime2. An additional histone deacetylase activity, that of the Set3/Hos2 complex, regulates the transcription of IME2 as well as NDT80 early in meiosis (Pijnappel et al., 2001). Deletion of SET3 or HOS2 has no effect during vegetative growth (although this might be due to repression by Sin3/Rpd3), but it leads to increased and advanced transcription of IME2 and NDT80, as well as moderate increase in the transcription of IME1 (Pijnappel et al., 2001). Consequently, these cells progress faster through MI, MII and asci formation (Pijnappel et al., 2001). Ime2 is subject to positive autoregulation that is most probably mediated by the MSE element present in its promoter and Ndt80 (see above, VA1). Protein stability: Ime2 is an extremely non-stable protein (Bolte et al., 2002; Guttmann-Raviv and Kassir, 2002) with a half-life of about 5 minutes (Guttmann-Raviv and Kassir, 2002). It is not known if the stability of Ime2 is subject to any regulation. Activity regulation: Ime2 is subject to phosphorylation (Benjamin et al., 2002; Guttmann-Raviv and Kassir, 2002). In vitro kinase assays reveals autophosphorylation (Benjamin et al., 2002; Guttmann-Raviv and Kassir, 2002; Kominami et al., 1993), but its effect on the activity and/or stability of Ime2 is not known. The kinase activity of Ime2 is negatively regulated by its C- 33
terminal non-essential domain (Kominami et al., 1993). This is deduced from the following observations: i. Over expression of an Ime2 protein truncated for this domain promotes meiosis in the presence of either nitrogen or glucose (Kominami et al., 1993), and ii. The in vitro-kinase activity of Ime2 is higher for a truncated Ime2 protein in comparison to the wt protein (Kominami et al., 1993). Thus, in the presence of nutrients Ime2 is less, or non-active. The nutrient signal is transmitted to the C-terminal domain through the Gα protein, Gpa2 (Donzeau and Bandlow, 1999). Ime2 specifically associates with the GTP bound Gpa2 (Donzeau and Bandlow, 1999), a form whose level is increased in the presence of glucose [for review see (Versele et al., 2001)]. In addition, the association between Gpa2 and Ime2 requires the presence of nitrogen (Donzeau and Bandlow, 1999). Cells deleted for GPA2 show similar phenotypes to cells over expressing the truncated Ime2 protein, namely, sporulation in the presence of glucose and nitrogen (Donzeau and Bandlow, 1999). Gpa2 associates with the glucose receptor, Gpr1, and transmits the glucose signal to adenylate cyclase [for review see (Pan et al., 2000)], however, the effect of Gpa2 on Ime2 is independent of PKA (Donzeau and Bandlow, 1999). This is deduced from the observation that the bcy1-tpk1 w1 mutation that leads to low activity of PKA does not suppress the reduction in sporulation exhibited by cells expressing the constitutive active Gpa2G132V protein (Donzeau and Bandlow, 1999). The in vitro kinase activity of Ime2 on histone H1 is decreased by the addition of recombinant Gpa2γS (Donzeau and Bandlow, 1999), suggesting that Gpa2 inhibits the kinase activity of Ime2 (Donzeau and Bandlow, 1999). In vitro kinase assays also demonstrate that Ime2 phosphorylates Gpa2 (Donzeau and Bandlow, 1999), but the role of this phosphorylation is not known. Ime2 kinase activity fluctuates in the meiotic cycle, it first peaks concomitantly with premeiotic DNA replication and then, concomitantly with nuclear division (Benjamin et al., 2002). The second increase in activity is regulated by Cdc28 (Benjamin et al., 2002). The activity of Ime2 is also regulated by Ids2 (Sia and Mitchell, 1995). Over expression of Ime2 in vegetative growth media is toxic (Bolte et al., 2002; Guttmann-Raviv and Kassir, 2002; Sia and Mitchell, 1995), and this toxicity is relived in cells deleted for IDS2 (Sia and Mitchell, 1995), suggesting that Ids2 is a positive regulator of Ime2. Ids2 is not required for meiosis (Sia and Mitchell, 1995), however, in its absence over expression of Ime2 (in the SK1 strain) leads to the transcription of only the early meiosis-specific genes, while middle and late genes remain silent and spores are not formed (Sia and Mitchell, 1995). This result suggests that the activity of Ime2 is distinctly regulated at early and middle meiotic times (Sia and Mitchell, 1995), in agreement with the finding of Benjamin et al., (Benjamin et al., 2002) reported above. The effect of Ids2 is mediated through the C-terminal domain of Ime2: Over expression of Ime2 truncated 34
Page 1 and 2: Transcriptional regulation of meios
Page 3 and 4: 3. Proteins required for the associ
Page 5 and 6: I. Introduction The budding yeast S
Page 7 and 8: et al., 2000). On the other hand, i
Page 9 and 10: the UCS4 element upstream of the CY
Page 11 and 12: egulator of Cyr1, CDC25 encodes the
Page 13 and 14: 1998). Furthermore, unlike IREu, IR
Page 15 and 16: In the absence of glucose Sok2 does
Page 17 and 18: autophosphorylation, including on a
Page 19 and 20: hours in SPM, followed by a decline
Page 21 and 22: 4. The SIN3, UME6, and RPD3 genes.
Page 23 and 24: 1993). Nevertheless, when Ime1 is t
Page 25 and 26: However, direct demonstration of ph
Page 27 and 28: 3. Proteins required for the associ
Page 29 and 30: heterologous promoter does not supp
Page 31 and 32: expressed only in the absence of gl
Page 33: structure of hCDK2 reveals that cyc
Page 37 and 38: is dependent on Ime2, but in cells
Page 39 and 40: VI. Transcriptional regulation of l
Page 41 and 42: The transcriptional activator that
Page 43 and 44: Functional interaction between Ime1
Page 45 and 46: Bowdish, K. S., and Mitchell, A. P.
Page 47 and 48: Foiani, M., Nadjar-Boger, E., Capon
Page 49 and 50: Jeffrey, P. D., Russo, A. A., Polya
Page 51 and 52: Lindgren, A., Bungard, D., Pierce,
Page 53 and 54: Pazin, M. J., and Kadonaga, J. T. (
Page 55 and 56: Shenhar, G. (2001). TRANSCRIPTIONAL
Page 57 and 58: Szent-Gyorgyi, C. (1995). A biparti
Page 59 and 60: Yoshida, M., Kawaguchi, H., Sakata,
Page 61 and 62: Fig. 4. The function of positive an
Page 63 and 64: Fig. 9. A schematic structure of IM
Page 65 and 66: activation by Ime2 is due to phosph
Page 67 and 68: MCK1 Protein kinase required for ef
Page 69: UME3 A cyclin C homolog that associ

Transcriptional regulation of meiosis in budding yeast

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