Academic journal article Genetics

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

Academic journal article Genetics

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

Article excerpt

ABSTRACT

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.

THE 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 been the discovery that a number of nonreplication proteins that associate with the DNA replication fork have been shown to have roles in the establishment of chromatin states (Groth et al. 2007). Another complementary model for the establishment of epigenetic states posits that DNA replication factors themselves have distinct roles in the establishment of different chromatin states. An excellent example of this has been the work on the origin recognition complex (ORC). The ORC has been shown to be a structural component of heterochromatin in yeast and has been shown in Drosophila to physically interact with Heterochromatin protein 1 (Hp1) and be involved in its correct localization (Pak et al. 1997; Huang et al. 1998; Shareef et al. 2001; Gerbi and Bielinsky 2002; Rusche et al. 2002). Finally, replication timing has been implicated in the establishment of chromatin structure with early S-phase replication being associated with euchromatin and late S-phase replication associated with heterochromatin (Hiratani and Gilbert 2009). …

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