Functional insight into the role of Orc6 in septin complex filament formation in<i>Drosophila</i>

Akhmetova, Katarina; Balasov, Maxim; Huijbregts, Richard P. H.; Chesnokov, Igor

doi:10.1091/mbc.e14-02-0734

Cited by 26 publications

(26 citation statements)

References 69 publications

(154 reference statements)

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“…The metazoan Orc6 consists of two domains, a larger N‐terminal domain which carries homology with TFIIB transcription factor and is important for DNA binding [Chesnokov et al, ; Balasov et al, ; Liu et al, ] and a shorter C‐terminal domain important for the function of Orc6 in cytokinesis [Prasanth et al, ; Chesnokov et al, ; Huijbregts et al, ; Bernal and Venkitaraman, ; Akhmetova et al, ]. The C‐terminal domain of Orc6 is also essential and sufficient for the interaction of Orc6 with core ORC [Bleichert et al, ].…”

Section: Resultsmentioning

confidence: 99%

“…Orc6 is also essential for cytokinesis in Drosophila and human cells [Prasanth et al, ; Chesnokov et al, ]. In Drosophila , Orc6 stimulates septin complex GTPase activity and polymerization during filament assembly through protein–protein interactions [Huijbregts et al, ; Akhmetova et al, ]. Metazoan Orc6 proteins consist of two functional domains: a larger N‐terminal domain important for binding of DNA and smaller C‐terminal domain important for protein‐protein interactions [Chesnokov et al, ; Balasov et al, ; Duncker et al, ; Bleichert et al, ].…”

Section: Introductionmentioning

confidence: 99%

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Drosophila model of Meier‐Gorlin syndrome based on the mutation in a conserved C‐Terminal domain of Orc6

Balasov

Akhmetova

Chesnokov

2015

American J of Med Genetics Pt A

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Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears, and skeletal abnormalities. Patients with MGS often carry mutations in the genes encoding the components of the pre-replicative complex such as Origin Recognition Complex (ORC) subunits Orc1, Orc4, Orc6, and helicase loaders Cdt1 and Cdc6. Orc6 is an important component of ORC and has functions in both DNA replication and cytokinesis. Mutation in conserved C-terminal motif of Orc6 associated with MGS impedes the interaction of Orc6 with core ORC. In order to study the effects of MGS mutation in an animal model system we introduced MGS mutation in Orc6 and established Drosophila model of MGS. Mutant flies die at third instar larval stage with abnormal chromosomes and DNA replication defects. The lethality can be rescued by elevated expression of mutant Orc6 protein. Rescued MGS flies are unable to fly and display multiple planar cell polarity defects.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Drosophila model of Meier‐Gorlin syndrome based on the mutation in a conserved C‐Terminal domain of Orc6

Balasov

Akhmetova

Chesnokov

2015

American J of Med Genetics Pt A

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“…The absence of SEPT7 destabilizes other core septins and prevents the formation of functional filaments. Although most of the septins, except the SEPT6 family, display intrinsic GTPase activity, nucleotide binding rather than GTPase activity has been implicated in septin filament formation (Versele and Thorner, 2004;Sirajuddin et al, 2009;Akhmetova et al, 2015). In addition, association of septins with membrane lipids and other cytoskeletal elements can influence filament formation (Kinoshita et al, 2002;Tanaka-Takiguchi et al, 2009;Bertin et al, 2010).…”

Section: Septin-independent Cytokinesis In Invertebrate Modelsmentioning

confidence: 99%

Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

Menon

Gaestel

2015

Journal of Cell Science

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Cytokinesis is the final step of cell division, and is a process that requires a precisely coordinated molecular machinery to fully separate the cytoplasm of the parent cell and to establish the intact outer cell barrier of the daughter cells. Among various cytoskeletal proteins involved, septins are known to be essential mediators of cytokinesis. In this Commentary, we present recent observations that specific cell divisions can proceed in the absence of the core mammalian septin SEPT7 and its Drosophila homolog Peanut (Pnut) and that thus challenge the view that septins have an essential role in cytokinesis. In the pnut mutant neuroepithelium, orthogonal cell divisions are successfully completed. Similarly, in the mouse, Sept7-null mutant early embryonic cells and, more importantly, planktonically growing adult hematopoietic cells undergo productive proliferation. Hence, as discussed here, mechanisms must exist that compensate for the lack of SEPT7 and the other core septins in a celltype-specific manner. Despite there being crucial non-canonical immune-relevant functions of septins, septin depletion is well tolerated by the hematopoietic system. Thus differential targeting of cytokinesis could form the basis for more specific anti-proliferative therapies to combat malignancies arising from cell types that require septins for cytokinesis, such as carcinomas and sarcomas, without impairing hematopoiesis that is less dependent on septin.

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“…Besides that, it was demonstrated that the C-terminal domain contains a motif which mediates an ORC6 interaction with the Pnut protein, a component of the septin complex [20]. ORC6 promotes septin polymerization due to its ability to form a dimer [102,103]. Although the molecular mechanism for the septin filament assembly still remains poorly understood, the results obtained so far provide strong evidence for the direct involvement of ORC6 in this process.…”

Section: Centrosome Duplication and Cytokinesismentioning

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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Functional insight into the role of Orc6 in septin complex filament formation inDrosophila

Abstract: Detailed roles of conserved septin motifs, GTP, and Orc6 in Drosophila septin complex functions are examined both in vitro and in vivo in a live animal. A novel mechanism of Orc6 regulation of septin filament formation is presented.

Cited by 26 publications

References 69 publications

Drosophila model of Meier‐Gorlin syndrome based on the mutation in a conserved C‐Terminal domain of Orc6

Drosophila model of Meier‐Gorlin syndrome based on the mutation in a conserved C‐Terminal domain of Orc6

Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

Nonreplicative functions of the origin recognition complex

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