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The origin recognition complex protein family.

Duncker BP, Chesnokov IN, McConkey BJ - Genome Biol. (2009)

Bottom Line: ORC proteins have also been found in the archaea, and the bacterial DnaA replication protein has ORC-like functional domains.In addition, ORC proteins function in epigenetic gene silencing through interactions with heterochromatin factors such as Sir1 in budding yeast and HP1 in higher eukaryotes.Current avenues of research have identified roles for ORC proteins in the development of neuronal and muscle tissue, and are probing their relationship to genome integrity.

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Affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada. bduncker@sciborg.uwaterloo.ca

ABSTRACT
Origin recognition complex (ORC) proteins were first discovered as a six-subunit assemblage in budding yeast that promotes the initiation of DNA replication. Orc1-5 appear to be present in all eukaryotes, and include both AAA+ and winged-helix motifs. A sixth protein, Orc6, shows no structural similarity to the other ORC proteins, and is poorly conserved between budding yeast and most other eukaryotic species. The replication factor Cdc6 has extensive sequence similarity with Orc1 and phylogenetic analysis suggests the genes that encode them may be paralogs. ORC proteins have also been found in the archaea, and the bacterial DnaA replication protein has ORC-like functional domains. In budding yeast, Orc1-6 are bound to origins of DNA replication throughout the cell cycle. Following association with Cdc6 in G1 phase, the sequential hydrolysis of Cdc6 - then ORC-bound ATP loads the Mcm2-7 helicase complex onto DNA. Localization of ORC subunits to the kinetochore and centrosome during mitosis and to the cleavage furrow during cytokinesis has been observed in metazoan cells and, along with phenotypes observed following knockdown with short interfering RNAs, point to additional roles at these cell-cycle stages. In addition, ORC proteins function in epigenetic gene silencing through interactions with heterochromatin factors such as Sir1 in budding yeast and HP1 in higher eukaryotes. Current avenues of research have identified roles for ORC proteins in the development of neuronal and muscle tissue, and are probing their relationship to genome integrity.

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ORC and its interactions with other pre-RC proteins at origins of DNA replication. Orc1-Orc5 are required for origin recognition and binding in S. cerevisiae, whereas Orc6 is dispensable in this regard [44]. In contrast, Orc6 is essential for ORC DNA binding in D. melanogaster [28]. Studies with both S. cerevisiae and human cells have indicated that Cdc6 interacts with ORC through the Orc1 subunit (indicated by a double arrow) [31,79,80]. This association increases the specificity of the ORC-origin interaction [20]. Further studies with S. cerevisiae suggest that hydrolysis of Cdc6-bound ATP promotes the association of Cdt1 with origins through an interaction with Orc6 (indicated by a double arrow) [25,31], and this in turn promotes the loading of Mcm2-7 helicase onto chromatin.
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Figure 3: ORC and its interactions with other pre-RC proteins at origins of DNA replication. Orc1-Orc5 are required for origin recognition and binding in S. cerevisiae, whereas Orc6 is dispensable in this regard [44]. In contrast, Orc6 is essential for ORC DNA binding in D. melanogaster [28]. Studies with both S. cerevisiae and human cells have indicated that Cdc6 interacts with ORC through the Orc1 subunit (indicated by a double arrow) [31,79,80]. This association increases the specificity of the ORC-origin interaction [20]. Further studies with S. cerevisiae suggest that hydrolysis of Cdc6-bound ATP promotes the association of Cdt1 with origins through an interaction with Orc6 (indicated by a double arrow) [25,31], and this in turn promotes the loading of Mcm2-7 helicase onto chromatin.

Mentions: Along with ORC subunit orthologs, additional Orc1-like proteins are widespread in eukaryotic species. The most notable of these is Cdc6, a replication factor that aids in loading the Mcm2-7 DNA helicase onto replication origins (Figure 3). In budding yeast, Cdc6 has strong similarity with a 270-amino-acid stretch of Orc1 [6], and phylogenetic analysis of a wide array of species suggests that the ORC1 and CDC6 genes may be paralogs [12]. As shown by a neighbor-joining tree based on AAA+ protein domains (discussed below), Orc1 is more closely related to Cdc6 than to other ORC subunits (Figure 4). In addition to Cdc6, which is well conserved among eukaryotes, some species-specific Orc1-like proteins have also been identified. These include budding yeast Sir3, a protein which mediates hetero-chromatin formation [6]. In Arabidopsis, paralogous ORC1 genes, termed ORC1a and ORC1b, have been found, and it appears that ORC1a is preferentially expressed in endoreplicating cells, whereas Orc1b expression is limited to proliferating cells [10].


The origin recognition complex protein family.

Duncker BP, Chesnokov IN, McConkey BJ - Genome Biol. (2009)

ORC and its interactions with other pre-RC proteins at origins of DNA replication. Orc1-Orc5 are required for origin recognition and binding in S. cerevisiae, whereas Orc6 is dispensable in this regard [44]. In contrast, Orc6 is essential for ORC DNA binding in D. melanogaster [28]. Studies with both S. cerevisiae and human cells have indicated that Cdc6 interacts with ORC through the Orc1 subunit (indicated by a double arrow) [31,79,80]. This association increases the specificity of the ORC-origin interaction [20]. Further studies with S. cerevisiae suggest that hydrolysis of Cdc6-bound ATP promotes the association of Cdt1 with origins through an interaction with Orc6 (indicated by a double arrow) [25,31], and this in turn promotes the loading of Mcm2-7 helicase onto chromatin.
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Related In: Results  -  Collection

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Figure 3: ORC and its interactions with other pre-RC proteins at origins of DNA replication. Orc1-Orc5 are required for origin recognition and binding in S. cerevisiae, whereas Orc6 is dispensable in this regard [44]. In contrast, Orc6 is essential for ORC DNA binding in D. melanogaster [28]. Studies with both S. cerevisiae and human cells have indicated that Cdc6 interacts with ORC through the Orc1 subunit (indicated by a double arrow) [31,79,80]. This association increases the specificity of the ORC-origin interaction [20]. Further studies with S. cerevisiae suggest that hydrolysis of Cdc6-bound ATP promotes the association of Cdt1 with origins through an interaction with Orc6 (indicated by a double arrow) [25,31], and this in turn promotes the loading of Mcm2-7 helicase onto chromatin.
Mentions: Along with ORC subunit orthologs, additional Orc1-like proteins are widespread in eukaryotic species. The most notable of these is Cdc6, a replication factor that aids in loading the Mcm2-7 DNA helicase onto replication origins (Figure 3). In budding yeast, Cdc6 has strong similarity with a 270-amino-acid stretch of Orc1 [6], and phylogenetic analysis of a wide array of species suggests that the ORC1 and CDC6 genes may be paralogs [12]. As shown by a neighbor-joining tree based on AAA+ protein domains (discussed below), Orc1 is more closely related to Cdc6 than to other ORC subunits (Figure 4). In addition to Cdc6, which is well conserved among eukaryotes, some species-specific Orc1-like proteins have also been identified. These include budding yeast Sir3, a protein which mediates hetero-chromatin formation [6]. In Arabidopsis, paralogous ORC1 genes, termed ORC1a and ORC1b, have been found, and it appears that ORC1a is preferentially expressed in endoreplicating cells, whereas Orc1b expression is limited to proliferating cells [10].

Bottom Line: ORC proteins have also been found in the archaea, and the bacterial DnaA replication protein has ORC-like functional domains.In addition, ORC proteins function in epigenetic gene silencing through interactions with heterochromatin factors such as Sir1 in budding yeast and HP1 in higher eukaryotes.Current avenues of research have identified roles for ORC proteins in the development of neuronal and muscle tissue, and are probing their relationship to genome integrity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada. bduncker@sciborg.uwaterloo.ca

ABSTRACT
Origin recognition complex (ORC) proteins were first discovered as a six-subunit assemblage in budding yeast that promotes the initiation of DNA replication. Orc1-5 appear to be present in all eukaryotes, and include both AAA+ and winged-helix motifs. A sixth protein, Orc6, shows no structural similarity to the other ORC proteins, and is poorly conserved between budding yeast and most other eukaryotic species. The replication factor Cdc6 has extensive sequence similarity with Orc1 and phylogenetic analysis suggests the genes that encode them may be paralogs. ORC proteins have also been found in the archaea, and the bacterial DnaA replication protein has ORC-like functional domains. In budding yeast, Orc1-6 are bound to origins of DNA replication throughout the cell cycle. Following association with Cdc6 in G1 phase, the sequential hydrolysis of Cdc6 - then ORC-bound ATP loads the Mcm2-7 helicase complex onto DNA. Localization of ORC subunits to the kinetochore and centrosome during mitosis and to the cleavage furrow during cytokinesis has been observed in metazoan cells and, along with phenotypes observed following knockdown with short interfering RNAs, point to additional roles at these cell-cycle stages. In addition, ORC proteins function in epigenetic gene silencing through interactions with heterochromatin factors such as Sir1 in budding yeast and HP1 in higher eukaryotes. Current avenues of research have identified roles for ORC proteins in the development of neuronal and muscle tissue, and are probing their relationship to genome integrity.

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