Orc6 Involved in DNA Replication, Chromosome Segregation, and Cytokinesis

Prasanth, Supriya G.; Prasanth, Kannanganattu V.; Stillman, Bruce

doi:10.1126/science.1072802

Cited by 204 publications

(208 citation statements)

References 24 publications

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“…The fact that inactivation of the Orc6 NLS prevents both nuclear localization of Orc6 and cell proliferation demonstrates that nuclear localization of Orc6 is essential to Orc6 function. In the absence of Orc6 function, cells accumulated both in G 1 and in G 2 or M phase, consistent with previous reports that siRNA suppression of either human or Drosophila Orc6 expression retards both DNA replication and cytokinesis (27,28).…”

Section: Nuclear Localization Of Orc6-humansupporting

confidence: 78%

Assembly of the Human Origin Recognition Complex Occurs through Independent Nuclear Localization of Its Components

Ghosh

Vassilev

Zhang

et al. 2011

Journal of Biological Chemistry

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Initiation of eukaryotic genome duplication begins when a six-subunit origin recognition complex (ORC) binds to DNA. However, the mechanism by which this occurs in vivo and the roles played by individual subunits appear to differ significantly among organisms. Previous studies identified a soluble human ORC(2-5) complex in the nucleus, an ORC(1-5) complex bound to chromatin, and an Orc6 protein that binds weakly, if at all, to other ORC subunits. Here we show that stable ORC(1-6) complexes also can be purified from human cell extracts and that Orc6 and Orc1 each contain a single nuclear localization signal that is essential for nuclear localization but not for ORC assembly. The Orc6 nuclear localization signal, which is essential for Orc6 function, is facilitated by phosphorylation at its cyclin-dependent kinase consensus site and by association with Kpna6/1, nuclear transport proteins that did not co-purify with other ORC subunits. These and other results support a model in which Orc6, Orc1, and ORC(2-5) are transported independently to the nucleus where they can either assemble into ORC(1-6) or function individually.

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Section: Nuclear Localization Of Orc6-humansupporting

confidence: 78%

Assembly of the Human Origin Recognition Complex Occurs through Independent Nuclear Localization of Its Components

Ghosh

Vassilev

Zhang

et al. 2011

Journal of Biological Chemistry

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“…Although it is unusual for a chromatin-associated factor to play a role in spindle organization, it is not unprecedented. For example, origin recognition complex protein 2 (ORC2) and ORC6 have, in addition to their activities at the replication origins, spindle-related functions at the centrosomes and kinetochores, respectively (Prasanth et al, 2002(Prasanth et al, , 2004. DNA repair factors such as BRCA1 were also shown to localize to the centrosomes and play a role in centrosome duplication (Xu et al, 1999;Fukasawa, 2005).…”

Section: Two Distinct Functions Of Cohesin In Mitosismentioning

confidence: 99%

Cohesin Associates with Spindle Poles in a Mitosis-specific Manner and Functions in Spindle Assembly in Vertebrate Cells

Kong

Ball

Sonoda

et al. 2009

MBoC

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Cohesin is an essential protein complex required for sister chromatid cohesion. Cohesin associates with chromosomes and establishes sister chromatid cohesion during interphase. During metaphase, a small amount of cohesin remains at the chromosome-pairing domain, mainly at the centromeres, whereas the majority of cohesin resides in the cytoplasm, where its functions remain unclear. We describe the mitosis-specific recruitment of cohesin to the spindle poles through its association with centrosomes and interaction with nuclear mitotic apparatus protein (NuMA). Overexpression of NuMA enhances cohesin accumulation at spindle poles. Although transient cohesin depletion does not lead to visible impairment of normal spindle formation, recovery from nocodazole-induced spindle disruption was significantly impaired. Importantly, selective blocking of cohesin localization to centromeres, which disrupts centromeric sister chromatid cohesion, had no effect on this spindle reassembly process, clearly separating the roles of cohesin at kinetochores and spindle poles. In vitro, chromosome-independent spindle assembly using mitotic extracts was compromised by cohesin depletion, and it was rescued by addition of cohesin that was isolated from mitotic, but not S phase, cells. The combined results identify a novel spindle-associated role for human cohesin during mitosis, in addition to its function at the centromere/kinetochore regions. INTRODUCTIONMitotic spindle formation is critical for proper chromosome congression, alignment, and segregation during cell division (Compton, 2000;Scholey et al., 2003;Kline-Smith and Walczak, 2004). Microtubules (MTs) undergo drastic changes in their dynamics and organization as the cell enters mitosis to form the bipolar spindle apparatus. As the nuclear membrane breaks down at the G2/M transition, interphase cytoskeletal MTs are destabilized, and mitotic spindle MTs nucleate from two opposing centrosomes/spindle poles with increased growth and turnover rates (Saxton et al., 1984;Zhai et al., 1996). This mitosis-specific change of microtubule behavior indicates the presence of cell cycle-specific regulators of spindles. Indeed, studies identified many important microtubule-associated proteins (MAPs) that regulate different aspects of mitotic spindle dynamics, such as the efficiency of MT nucleation and minus-end focusing at spindle poles, MT plus-and minus-end dynamics, and overall spindle stability (Kline-Smith and Walczak, 2004). However, the intricate regulatory mechanisms for spindle organization are not completely understood, and there are most likely additional factors that contribute to proper spindle regulation during mitosis.Cohesin is a conserved and essential multiprotein complex required for sister chromatid cohesion (Losada et al., 1998;Uhlmann and Nasmyth, 1998;Toth et al., 1999). Genetic studies in both yeast and metazoans revealed that inhibition of cohesin function leads to premature separation of sister chromatids, chromosome misalignment, and meloteric attachment of spindles to...

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“…Immunostaining of cells with antibodies against ORC6 revealed that a considerable portion of this protein is present in the cytoplasm and is localized to the cell membrane and in the cleavage furrow [20,21]. ORC6 depletion in D. melanogaster cells results in defects in cytokinesis [66].…”

Section: Centrosome Duplication and Cytokinesismentioning

confidence: 99%

“…In the last few decades, involvement of ORC in numerous highly diverse cellular functions was discovered, e. g. the formation of heterochromatin, chromosome condensation and segregation, centrosome duplication, cytokinesis and mRNA nuclear export [14–17]. The sub-complexes or the individual subunits of ORC are localized not only in nuclei and on the mitotic chromosomes, but in the cytoplasm as well [18–21]. Interestingly, ORC subunits have also been detected in terminally differentiated mammalian cells that do not undergo subsequent cell divisions, for example, cardiomyocytes and neurons [22].…”

Section: Introductionmentioning

confidence: 99%

Nonreplicative functions of the origin recognition complex

Popova

Brechalov

Георгиева

et al. 2018

Nucleus

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Origin recognition complex (ORC), a heteromeric six-subunit complex, is the central component of the eukaryotic pre-replication complex. Recent data from yeast, frogs, flies and mammals present compelling evidence that ORC and its individual subunits have nonreplicative functions as well. The majority of these functions, such as heterochromatin formation, chromosome condensation, and segregation are dependent on ORC-DNA interactions. Furthermore, ORC is involved in the control of cell division via its participation in centrosome duplication and cytokinesis. Recent findings have also demonstrated a direct interaction between ORC and mRNPs and highlighted an essential role of ORC in mRNA nuclear export. Along with the growth of evolutionary complexity of organisms, ORC complex functions become more elaborate and new functions of the ORC sub-complexes and individual subunits have emerged.

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Orc6 Involved in DNA Replication, Chromosome Segregation, and Cytokinesis

Cited by 204 publications

References 24 publications

Assembly of the Human Origin Recognition Complex Occurs through Independent Nuclear Localization of Its Components

Assembly of the Human Origin Recognition Complex Occurs through Independent Nuclear Localization of Its Components

Cohesin Associates with Spindle Poles in a Mitosis-specific Manner and Functions in Spindle Assembly in Vertebrate Cells

Nonreplicative functions of the origin recognition complex

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