The origin recognition complex is dispensable for endoreplication in
            <i>Drosophila</i>

Park, So Young; Asano, Maki

doi:10.1073/pnas.0805189105

Cited by 58 publications

(80 citation statements)

References 49 publications

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“…No imaginal discs were detected in late third instar larvae of mutant animals. These phenotypes represent severe proliferation defects also observed in other replication initiation factor mutants (24,(26)(27)(28)(29)(30).…”

Section: Orc6 Mutant Is Defective In Dna Replication and Arrests In Bmentioning

confidence: 58%

Functional analysis of an Orc6 mutant in Drosophila

Balasov

Huijbregts

Chesnokov

2009

Proc. Natl. Acad. Sci. U.S.A.

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The origin recognition complex (ORC) is a 6-subunit complex required for the initiation of DNA replication in eukaryotic organisms. ORC is also involved in other cell functions. The smallest Drosophila ORC subunit, Orc6, is important for both DNA replication and cytokinesis. To study the role of Orc6 in vivo, the orc6 gene was deleted by imprecise excision of P element. Lethal alleles of orc6 are defective in DNA replication and also show abnormal chromosome condensation and segregation. The analysis of cells containing the orc6 deletion revealed that they arrest in both the G 1 and mitotic stages of the cell cycle. Orc6 deletion can be rescued to viability by a full-length Orc6 transgene. The expression of mutant transgenes of Orc6 with deleted or mutated C-terminal domain results in a release of mutant cells from G 1 arrest and restoration of DNA replication, indicating that the DNA replication function of Orc6 is associated with its N-terminal domain. However, these mutant cells accumulate at mitosis, suggesting that the C-terminal domain of Orc6 is important for the passage through the M phase. In a cross-species complementation experiment, the expression of human Orc6 in Drosophila Orc6 mutant cells rescued DNA replication, suggesting that this function of the protein is conserved among metazoans.DNA replication ͉ ORC ͉ Chromatin T he hexameric origin recognition complex (ORC) is an essential component for eukaryotic DNA replication. It was originally discovered in Saccharomyces cerevisiae, and subsequent studies both in yeast and in higher eukaryotes laid the foundation for understanding the functions of this important key initiation factor. ORC binds to origin sites in an ATP-dependent manner and directs the assembly of the prereplicative complex (pre-RC) at the origins (1, 2). ORC subunits and/or complete ORC complexes have also been identified in many metazoan species (1, 3), suggesting the existence of common mechanisms for the initiation of DNA replication in all eukaryotes. ORC genes are essential for cell survival. Mutational analysis of ORC-related genes in yeast and in higher eukaryotes reveals defects in DNA replication (reviewed in refs.

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Section: Orc6 Mutant Is Defective In Dna Replication and Arrests In Bmentioning

confidence: 58%

Functional analysis of an Orc6 mutant in Drosophila

Balasov

Huijbregts

Chesnokov

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Another DNA replication mutation in mcm6 also results in smaller larvae, most likely due to its role in endoreplication (Schwed et al 2002). Smaller size in larvae may also be due to defects in the proliferation of normal diploid imaginal disks as is the case with orc1 mutants (Park and Asano 2008).…”

Section: Mcm10mentioning

confidence: 99%

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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“…Because of the potential presence of low levels of maternally stored topo IIIα, endoreplication either does not require topo IIIα or low levels of topo IIIα would suffice. Interestingly, the origin recognition complex components Orc1 and Orc2 are also essential for mitotic cell division, and the endoreplication was not affected in their null mutants (22). (Table S1).…”

Section: The Amino Terminus Of Topo Iiiα Contains a Mitochondrial Importmentioning

confidence: 99%

Drosophila topo IIIα is required for the maintenance of mitochondrial genome and male germ-line stem cells

Wu¹,

Feng

Hsieh³

2010

Proc. Natl. Acad. Sci. U.S.A.

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Topoisomerase IIIα (topo IIIα), a member of the conserved Type IA subfamily of topoisomerases, is required for the cell proliferation in mitotic tissues, but has a lesser effect on DNA endoreplication. The top3α gene encodes two forms of protein by utilizing alternative translation initiation sites: one (short form) with the nuclear localization signal only, exclusively localized in the nuclei, and the other (long form), retaining a mitochondrial import sequence at the N-terminus and the nuclear localization sequence at the C-terminus, localized primarily in the mitochondria, though with a small portion in the nuclei. Both forms of topo IIIα can rescue the viability of null mutants of top3α. No apparent defect is associated with the flies rescued by the long form; short-form-rescued flies (referred to as M1L), however, exhibit defects in fertilities. M1L females are sterile. They can lay eggs but with mitochondrial DNA (mtDNA) copy number and ATP content decreased by 20-and 2-to 3-fold, respectively, and they fail to hatch. Of the newly eclosed M1L males, 33% are completely sterile, whereas the rest have residual fertilities that are quickly lost in 6 days. The fertility loss of M1L males is caused by the disruption of the individualization complex and a progressive loss of germ-line stem cells. This study implicates topo IIIα in the maintenance of mtDNA and male germ-line stem cells, and thus is a causative candidate for genetic disorders associated with mtDNA depletion.mtDNA depletion | DNA replication | DNA segregation | topoisomerase I ntertwining of DNA duplex provides an elegant means to store and transmit genetic information. However, because of this bihelical structure, the transaction of genetic information leads to DNA entanglement such as supercoiling, knotting, and catenation. DNA topoisomerases are nature's solution for resolving the topological problems associated with DNA metabolism. Based on structure and mechanism, there are two main groups of these enzymes (1, 2). Type I topoisomerases can reversibly cleave one DNA strand at a time, and type II enzymes are able to generate transient double strand breaks and transport another DNA segment through the reversible breaks. There are additional subtypes for each group. Bacterial topo I/III and eukaryotic topo III belong to type IA enzymes, and they work via a mechanism of strand passage through an enzyme-bridged single strand break. There are two isozymes of topo III, α and β, in metazoans: topo IIIα is essential for viability, and topo IIIβ is not (3, 4). Eucaryotic topo I is classified as type IB enzymes, and it forms an evolutionarily distinct class when compared with type IA enzymes, presumably a descendent of site-specific recombinases in bacteria (5). These enzymes work by generating a strand break where protein is linked to the 3 0 -phosphoryl end, allowing the free 5 0 end to undergo a restrained rotation around the nonscissile strand (6). Type IB can thus serve as an efficient swivel to remove supercoiling accumulated during replication or tr...

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The origin recognition complex is dispensable for endoreplication in Drosophila

Cited by 58 publications

References 49 publications

Functional analysis of an Orc6 mutant in Drosophila

Functional analysis of an Orc6 mutant in Drosophila

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

Drosophila topo IIIα is required for the maintenance of mitochondrial genome and male germ-line stem cells

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