Dual Roles for Mcm10 in DNA Replication Initiation and Silencing at the Mating-type Loci

Douglas, Nancy L.; Dozier, Samantha K.; Donato, Justin J.

doi:10.1007/s11033-005-2312-x

Cited by 13 publications

(20 citation statements)

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“…Moreover, the possible reason similar defects are not observed in the Mcm10 d08029 allele is due to the fact that the S-phase delay is not severe enough in the early embryo to manifest as a defect. However, given that Mcm10 has been shown to have multiple roles in S phase, then it is more likely that the differences in these early embryos are a reflection of these additional Mcm10 functions (Wohlschlegel et al 2002;Gregan et al 2003;Lee et al 2003;Bielinsky 2004, 2006;Sawyer et al 2004;Douglas et al 2005;Liachko and Tye 2005;Zhu et al 2007;Park et al 2008a,b;Liachko and Tye 2009;Xu et al 2009). In light of previous studies that demonstrated a role for Mcm10 in chromosome condensation, interaction with Hp1, and defects in heterochromatin formation (Christensen and Tye 2003;Tye 2005, 2009), it is compelling to speculate that the defects observed in early embryos may not be due only to a direct role in DNA replication for Mcm10 but may also reflect a role in chromosome condensation and heterochromatin formation during S phase.…”

Section: Discussionmentioning

confidence: 99%

“…Recently evidence has been uncovered that points to an involvement of Mcm10 in chromatin structure. Work using S. cerevisiae has demonstrated that Mcm10 is involved in transcriptional repression of the matingtype loci and links DNA replication proteins to heterochromatin formation (Douglas et al 2005;Tye 2005, 2009). Also pointing to a possible role in chromatin structure and chromosome condensation is that the depletion of Mcm10 in Drosophila tissue culture cells results in undercondensed metaphase chromosomes (Christensen and Tye 2003).…”

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Multiple Functions for Drosophila Mcm10 Suggested Through Analysis of Two Mcm10 Mutant Alleles

et al. 2010

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DNA replication and the correct packaging of DNA into different states of chromatin are both essential processes in all eukaryotic cells. High-fidelity replication of DNA is essential for the transmission of genetic material to cells. Likewise the maintenance of the epigenetic chromatin states is essential to the faithful reproduction of the transcriptional state of the cell. It is becoming more apparent that these two processes are linked through interactions between DNA replication proteins and chromatin-associated proteins. In addition, more proteins are being discovered that have dual roles in both DNA replication and the maintenance of epigenetic states. We present an analysis of two Drosophila mutants in the conserved DNA replication protein Mcm10. A hypomorphic mutant demonstrates that Mcm10 has a role in heterochromatic silencing and chromosome condensation, while the analysis of a novel C-terminal truncation allele of Mcm10 suggests that an interaction with Mcm2 is not required for chromosome condensation and heterochromatic silencing but is important for DNA replication.T HE essential process of DNA replication does not occur in a vacuum; rather, it takes place within the context of the cell. More specifically, DNA replication occurs within the context of chromatin: an integrated network of DNA-associated proteins that have roles in packaging DNA, controlling transcription, and maintaining genome integrity. The maintenance and manipulation of these chromatin proteins are, like DNA replication, an essential process. The packaging of DNA has significant consequences for the transcriptional state of the underlying DNA. Repression or activation of different regions of the genome through packaging as open euchromatin or as repressive heterochromatin is cell type specific (Fraser et al. 2009;Minard et al. 2009). Moreover, these transcriptional states must be maintained and passed on to daughter cells during mitosis. If not passed on faithfully, genome instability and/or transcriptional misregulation can occur, both of which may lead to defects in cell proliferation, cancer, and other disease states ( Jones et al. 2007;Hirst and Marra 2009).By necessity, the process of DNA replication requires unencumbered access to the nitrogenous bases that make up the DNA strand. As a result, chromatin proteins must be removed. In the wake of the DNA replication fork this nascent DNA must be repackaged to recapitulate the previous chromatin state. While DNA replication benefits from complementary base pairing to build a DNA molecule through semiconservative replication, the reestablishment of epigenetic states occurs through more subtle and varied mechanisms (Groth et al. 2007). One central question in reconciling the processes of DNA replication and the establishment and/or maintenance of chromatin states is how are these processes linked? One model suggests that DNA replication proteins interact with separate chromatin establishment factors, thereby spatially linking the two processes. Supporting this model has ...

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Section: Discussionmentioning

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Multiple Functions for Drosophila Mcm10 Suggested Through Analysis of Two Mcm10 Mutant Alleles

et al. 2010

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“…At restrictive temperature, mcm10 cells arrest at the end of S phase with aberrant DNA structures (Merchant et al 1997;Kawasaki et al 2000). Recently, Mcm10 has been implicated to function in chromatin structure in yeast as well as Drosophila melanogaster (Christensen and Tye 2003;Douglas et al 2005;Liachko and Tye 2005). In Drosophila, Mcm10 interacts with HP-1, an important heterochromatin protein (Christensen and Tye 2003), while in yeast Mcm10 interacts with Sir2 (Douglas et al 2005;Liachko and Tye 2005).…”

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confidence: 99%

“…Recently, Mcm10 has been implicated to function in chromatin structure in yeast as well as Drosophila melanogaster (Christensen and Tye 2003;Douglas et al 2005;Liachko and Tye 2005). In Drosophila, Mcm10 interacts with HP-1, an important heterochromatin protein (Christensen and Tye 2003), while in yeast Mcm10 interacts with Sir2 (Douglas et al 2005;Liachko and Tye 2005). In addition, genetic experiments suggest that the silencing function of Mcm10 is separate from its replication function (Douglas et al 2005;Liachko and Tye 2005).…”

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Mcm10 Mediates the Interaction Between DNA Replication and Silencing Machineries

Tye

2009

Genetics

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The connection between DNA replication and heterochromatic silencing in yeast has been a topic of investigation for .20 years. While early studies showed that silencing requires passage through S phase and implicated several DNA replication factors in silencing, later works showed that silent chromatin could form without DNA replication. In this study we show that members of the replicative helicase (Mcm3 and Mcm7) play a role in silencing and physically interact with the essential silencing factor, Sir2, even in the absence of DNA replication. Another replication factor, Mcm10, mediates the interaction between these replication and silencing proteins via a short C-terminal domain. Mutations in this region of Mcm10 disrupt the interaction between Sir2 and several of the Mcm2-7 proteins. While such mutations caused silencing defects, they did not cause DNA replication defects or affect the association of Sir2 with chromatin. Our findings suggest that Mcm10 is required for the coupling of the replication and silencing machineries to silence chromatin in a context outside of DNA replication beyond the recruitment and spreading of Sir2 on chromatin.

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Structural Biology of Replication Initiation Factor Mcm10

Stauffer

Eichman

2012

Subcellular Biochemistry

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Minichromosome maintenance protein 10 (Mcm10) is a non-enzymatic replication factor required for proper assembly of the eukaryotic replication fork. Mcm10 interacts with single-stranded and double-stranded DNA, polymerase α, and Mcm2-7, and is important for activation of the pre-replicative complex and recruitment of subsequent proteins to the origin at the onset of S-phase. In addition, Mcm10 has recently been implicated in coordination of helicase and polymerase activities during replication fork progression. The nature of Mcm10's involvement in these activities, whether direct or indirect, remains unknown. However, recent biochemical and structural characterization of Mcm10 from multiple organisms has provided insights into how Mcm10 utilizes a modular architecture to act as a replisome scaffold, which helps to define possible roles in origin DNA melting, pol α recruitment and coordination of enzymatic activities during elongation.

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Dual Roles for Mcm10 in DNA Replication Initiation and Silencing at the Mating-type Loci

Cited by 13 publications

References 17 publications

Multiple Functions for Drosophila Mcm10 Suggested Through Analysis of Two Mcm10 Mutant Alleles

Multiple Functions for Drosophila Mcm10 Suggested Through Analysis of Two Mcm10 Mutant Alleles

Mcm10 Mediates the Interaction Between DNA Replication and Silencing Machineries

Structural Biology of Replication Initiation Factor Mcm10

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