Evidence for a Role of MCM (Mini-chromosome Maintenance)5 in Transcriptional Repression of Sub-telomeric and Ty-proximal Genes in Saccharomyces cerevisiae

The MCM (mini-chromosome maintenance) genes have a well established role in the initiation of DNA replication and in the elongation of replication forks in Saccharomyces cerevisiae. In this study we demonstrate elevated expression of sub-telomeric and Ty retrotransposon-proximal genes in two mcm5 strains. This pattern of up-regulated genes resembles the genome-wide association of MCM proteins to chromatin that was reported earlier. We link the altered gene expression in mcm5 strains to a reversal of telomere position effect (TPE) and to remodeling of sub-telomeric and Ty chromatin. We also show a suppression of the Ts phenotype of a mcm5 strain by the high copy expression of the TRA1 component of the chromatin-remodeling SAGA/ADA (SPT-ADA-GCN5 acetylase/ADAptor). We propose that MCM proteins mediate the establishment of silent chromatin domains around telomeres and Ty retrotransposons. The MCM (mini-chromosome maintenance) genes have a well established role in the initiation of DNA replication and in the elongation of replication forks in Saccharomyces cerevisiae. In this study we demonstrate elevated expression of sub-telomeric and Ty retrotransposon-proximal genes in two mcm5 strains. This pattern of up-regulated genes resembles the genome-wide association of MCM proteins to chromatin that was reported earlier. We link the altered gene expression in mcm5 strains to a reversal of telomere position effect (TPE) and to remodeling of sub-telomeric and Ty chromatin. We also show a suppression of the Ts phenotype of a mcm5 strain by the high copy expression of the TRA1 component of the chromatin-remodeling SAGA/ADA (SPT-ADA-GCN5 acetylase/ADAptor). We propose that MCM proteins mediate the establishment of silent chromatin domains around telomeres and Ty retrotransposons. MCM 1The abbreviations used are: MCM, mini-chromosome maintenance; ORC, origin recognition complex; CDC, cell division cycle; LTR, long terminal repeat; TPE, telomere position effect; SIR, silencing information region; FOA, fluorotic acid; FOAR, FOA-resistant; COS, conserved sequences at telomeres; ORF, open reading frame; HM, mating type loci; pol, polymerase; STAT1, signal transducers and activators of transcription 1; ARS, autonomously replicating sequence; SAGA/ADA, SPT-ADA-GCN5 acetylase ADAptor. (mini-chromosome maintenance) genes had been identified in screens for Saccharomyces cerevisiae mutants, which displayed high rates of minichromosome loss (1Tye B.K. Methods. 1999; 18: 329-334Crossref PubMed Scopus (33) Google Scholar). MCM2-MCM7 homologues were subsequently found in all eukaryotes. It is believed that MCM proteins act as a component of the licensing machinery, which limits the occurrence of DNA replication to once per cell cycle (2Lei M. Tye B.K. J. Cell Sci. 2001; 114: 1447-1454Crossref PubMed Google Scholar, 3Labib K. Diffley J.F. Curr. Opin. Genet. Dev. 2001; 11: 64-70Crossref PubMed Scopus (125) Google Scholar). MCM proteins form pre-replicative complexes at active as well as silent origins in S. cerevisiae or on un-replicated DNA in higher eukaryotes in a manner dependent on origin recognition complex (ORC) and Cdc6 (2Lei M. Tye B.K. J. Cell Sci. 2001; 114: 1447-1454Crossref PubMed Google Scholar, 3Labib K. Diffley J.F. Curr. Opin. Genet. Dev. 2001; 11: 64-70Crossref PubMed Scopus (125) Google Scholar). Activation of these pre-replicative complexes by protein kinases is required for initiation of replication (2Lei M. Tye B.K. J. Cell Sci. 2001; 114: 1447-1454Crossref PubMed Google Scholar, 3Labib K. Diffley J.F. Curr. Opin. Genet. Dev. 2001; 11: 64-70Crossref PubMed Scopus (125) Google Scholar). Removal of the MCM complex from origins at the time of initiation is believed to limit origin firing until the next cell cycle when the pre-replicative complex is re-established (2Lei M. Tye B.K. J. Cell Sci. 2001; 114: 1447-1454Crossref PubMed Google Scholar, 3Labib K. Diffley J.F. Curr. Opin. Genet. Dev. 2001; 11: 64-70Crossref PubMed Scopus (125) Google Scholar). MCM proteins also seem to have a post-initiation role in DNA replication as indicated by their association with moving replication forks (4Aparicio O.M. Weinstein D.M. Bell S.P. Cell. 1997; 91: 59-69Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar) and by the requirement for their uninterrupted function for fork progression in S. cerevisiae (5Labib K. Tercero J.A. Diffley J.F. Science. 2000; 288: 1643-1647Crossref PubMed Scopus (523) Google Scholar). In vitro assembled MCM complexes have also been shown to have DNA helicase activity consistent with a role in both melting of origin DNA and unwinding during fork elongation (3Labib K. Diffley J.F. Curr. Opin. Genet. Dev. 2001; 11: 64-70Crossref PubMed Scopus (125) Google Scholar). Some of the properties of MCM proteins suggest that they may have functions that extend beyond the regulation of DNA replication. They are 100- to 1000-fold more abundant than the estimated number of origins in S. cerevisiae (6Lei M. Kawasaki Y. Tye B.K. Mol. Cell. Biol. 1996; 16: 5081-5090Crossref PubMed Scopus (155) Google Scholar, 7Young M.R. Tye B.K. Mol. Biol. Cell. 1997; 8: 1587-1601Crossref PubMed Scopus (68) Google Scholar) and mammals (8Burkhart R. Schulte D. Hu D. Musahl C. Goehring F. Knippers R. Eur. J. Biochem. 1995; 228: 431-438Crossref PubMed Scopus (119) Google Scholar, 9Todorov I.T. Attaran A. Kearsey S.E. J. Cell Biol. 1995; 129: 1433-1445Crossref PubMed Scopus (204) Google Scholar). Mammalian MCMs have been reported to associate with large complexes containing or contacting RNA polymerase II and general pol II transcription factors (10Yankulov K. Todorov I. Romanowski P. Licatalosi D. Cilli K. McCracken S. Laskey R. Bentley D.L. Mol. Cell. Biol. 1999; 19: 6154-6163Crossref PubMed Scopus (74) Google Scholar, 11Holland L. Gauthier L. Bell-Rogers P. Yankulov K. Eur. J. Biochem. 2002; 269: 5192-5202Crossref PubMed Scopus (27) Google Scholar), with the MAT1 component of CAK/TFIIH (12Wang Y. Xu F. Hall F.L. FEBS Lett. 2000; 484: 17-21Crossref PubMed Scopus (11) Google Scholar), with the transcriptional activator STAT1 (13Zhang J.J. Zhao Y. Chait B.T. Lathem W.W. Ritzi M. Knippers R. Darnell Jr., J.E. EMBO J. 1998; 17: 6963-6971Crossref PubMed Scopus (191) Google Scholar, 14DaFonseca C.J. Shu F. Zhang J.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3034-3039Crossref PubMed Scopus (69) Google Scholar), and with the tumor suppressor pRB (15Sterner J.M. Dew-Knight S. 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P. 2001; PubMed Scopus Google Scholar). of the silent in all is by a which expression of from a high copy and is by the complex and the Dev. 2002; 16: PubMed Scopus Google Scholar, A. L. M. P. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). in TPE, Ty suppression is that in a cell all or of the Ty are Dev. 2002; 16: PubMed Scopus Google Scholar, A. L. M. P. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). In this we gene expression in mcm5 We found that a number of genes in the of telomeres and Ty were up-regulated at the in two of the This with chromatin remodeling of the and reversal of and strains used in this study are in I. and were by the mcm5 strains with L. R. D. J. M. Bentley D. Yankulov K. 2002; Google Scholar) by to were on and on at and were by and with O.M. Cell. Full Text PDF PubMed Scopus Google Scholar) by and or by O.M. Cell. Full Text PDF PubMed Scopus Google Scholar) by and on is next to the of the of and the of O.M. Cell. 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Biol. 2002; PubMed Scopus Google Scholar). the suppression of the Ts phenotype of by TRA1 the of suppression of sub-telomeric and that MCM proteins may with chromatin remodeling factors that gene In this we show that in to of genes that are to telomeres and We estimated that these are to cell cycle regulation of gene expression and are a of of the next to We also show that the gene expression pattern with chromatin remodeling in the sub-telomeric and of the and with reversal of are for two the suggest role for the MCM genes in transcriptional in to their well function in initiation of DNA replication and in replication fork elongation (2Lei M. Tye B.K. J. Cell Sci. 2001; 114: 1447-1454Crossref PubMed Google Scholar, 3Labib K. Diffley J.F. Curr. Opin. Genet. Dev. 2001; 11: 64-70Crossref PubMed Scopus (125) Google Scholar). are consistent with a study that may act as a of cell cycle and K. we demonstrate a in the of Ty and We suggest that may a in the gene expression telomeres and Ty retrotransposons. we propose that is DNA replication that transcriptional in study is the gene expression are to of DNA replication or of the cell In are two on the DNA replication and chromatin The that chromatin silencing and DNA replication or a during 2002; PubMed Google Scholar, O.M. Dev. 8: PubMed Scopus Google Scholar, S. J. Science. 1997; PubMed Scopus Google Scholar). that have a effect on 2002; PubMed Google Scholar) and is at with this DNA replication is required to silencing at the mating type J. Science. 2001; PubMed Scopus Google Scholar) and telomeres their transcriptional during D. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). to in the effect of that DNA replication and their to silencing at J. 1999; Google Scholar). In the of and their functions in silencing and DNA replication are A. J. 1997; PubMed Google Scholar, M. M.R. J. Science. 1995; PubMed Scopus Google Scholar). is also both and for the establishment of silencing A. Bell S.P. Dev. 2002; 16: PubMed Scopus Google Scholar). and propose the that replication proteins have a role in silencing by with factors that chromatin J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar, J. 1999; Google Scholar, J. Science. 2001; PubMed Scopus Google Scholar, M.R. Science. 2001; PubMed Scopus Google Scholar). of DNA replication the establishment of silent chromatin. In with the we DNA replication and cell on and gene on the all mcm5 strains we have a mini-chromosome P. Tye B.K. PubMed Google Scholar, A. D. Dev. PubMed Scopus Google Scholar, Y. D. Tye B.K. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) that is of DNA replication (1Tye B.K. Methods. 1999; 18: 329-334Crossref PubMed Scopus (33) Google Scholar), and of and genes was cell and of the replication and gene We to the cell cycle regulation of gene expression and sub-telomeric and In we higher than the number of with expression at in and Zhang K. D. Mol. Biol. Cell. 1998; PubMed Scopus Google Scholar). It is that or a or which are for Tye B.K. Dev. PubMed Scopus Google Scholar, M. Tye B.K. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. J. Cell Sci. 1999; PubMed Google Scholar), to this gene expression pattern in the and It is that of the genes in II are to telomeres or Ty and that of the and sub-telomeric genes had been as cell genes In of the genes to DNA of DNA replication It is that a the genes and the and sub-telomeric is Ty expression to cell cycle that in this the the of up-regulated genes in the mcm5 is of the of complexes to chromatin J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar). In this study a higher than association of complexes with sub-telomeric chromatin and chromatin around Ty and was found J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar). of the as origins and a of are J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar). We found a higher than number of up-regulated genes in the mcm5 in the of the that show higher association of MCM proteins and J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google indicated that a of the up-regulated genes in the and strains are next to a J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar). we with of active or sequences on We propose that at of the in sub-telomeric chromatin and to Ty in chromatin that MCM proteins with chromatin remodeling factors that chromatin of of the a and of gene expression in the This effect is on a than on It is that we of next to telomeres and Ty It that of sub-telomeric and chromatin is a of all of these The of this function of the MCM proteins is The of mcm5 with TRA1 the of This complex is a that is required for of a the requirement of and activity for gene as well J. C.J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). of chromatin factors also We also found a higher than of up-regulated genes from and genes and from genes the in the the of these genes is the is than in the of sub-telomeric and Ty It that chromatin at these also to complexes at higher J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar). this we a MCM and of transcription around and the is in the of up-regulated in II are the genes in the mating type of these is by that are to S. J. Science. PubMed Scopus Google Scholar) and MCMs J.J. Bell S.P. O.M. Science. 2001; PubMed Scopus Google Scholar). is that had is that suppression of these is to in The is in with study in which the A. D. Dev. PubMed Scopus Google Scholar) to silencing at J. 1999; Google Scholar). have of MCM proteins with a transcriptional activator (13Zhang J.J. Zhao Y. Chait B.T. Lathem W.W. Ritzi M. Knippers R. Darnell Jr., J.E. EMBO J. 1998; 17: 6963-6971Crossref PubMed Scopus (191) Google Scholar, 14DaFonseca C.J. Shu F. Zhang J.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3034-3039Crossref PubMed Scopus (69) Google Scholar) or RNA pol II and general transcription factors (10Yankulov K. Todorov I. Romanowski P. Licatalosi D. Cilli K. McCracken S. Laskey R. Bentley D.L. Mol. Cell. Biol. 1999; 19: 6154-6163Crossref PubMed Scopus (74) Google Scholar, 11Holland L. Gauthier L. Bell-Rogers P. Yankulov K. Eur. J. Biochem. 2002; 269: 5192-5202Crossref PubMed Scopus (27) Google Scholar) in higher eukaryotes. RNA pol II and was also L. R. D. J. M. Bentley D. Yankulov K. 2002; Google Scholar). We the that the effect of in on gene expression in the and is by of chromatin in of the is that the are by the of the MCM proteins with factors that are in pol II the MCM chromatin and gene We K. for and on the and R. D. A. J. L. and R. for and

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