A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation

In eukaryotes, DNA replication requires the origin recognition complex (ORC), a six-subunit assembly that promotes replisome formation on chromosomal origins. Despite extant homology between certain subunits, the degree of structural and organizational overlap between budding yeast and metazoan ORC...

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Bibliographic Details
Published in:eLife 2013-10, Vol.2, p.e00882
Main Authors: Bleichert, Franziska, Balasov, Maxim, Chesnokov, Igor, Nogales, Eva, Botchan, Michael R, Berger, James M
Format: Article
Language:English
Subjects:
Animals
BASIC BIOLOGICAL SCIENCES
Biochemistry
Biophysics and Structural Biology
C-Terminus
Cell cycle
Congenital Microtia - genetics
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA replication
Drosophila
Drosophila melanogaster
Dwarfism
Electron microscopy
Gorlin syndrome
Growth Disorders - genetics
Hexamers
Homology
Humans
Insects
Licenses
Life Sciences & Biomedicine - Other Topics
Meier-Gorlin syndrome
Micrognathism - genetics
Microscopy, Electron
Mutation
ORC
origin licensing
Origin recognition complex
Origin Recognition Complex - genetics
Origin Recognition Complex - ultrastructure
Patella - abnormalities
Proteins
Replication origins
Saccharomyces cerevisiae
Yeast
Zebrafish
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Summary:In eukaryotes, DNA replication requires the origin recognition complex (ORC), a six-subunit assembly that promotes replisome formation on chromosomal origins. Despite extant homology between certain subunits, the degree of structural and organizational overlap between budding yeast and metazoan ORC has been unclear. Using 3D electron microscopy, we determined the subunit organization of metazoan ORC, revealing that it adopts a global architecture very similar to the budding yeast complex. Bioinformatic analysis extends this conservation to Orc6, a subunit of somewhat enigmatic function. Unexpectedly, a mutation in the Orc6 C-terminus linked to Meier-Gorlin syndrome, a dwarfism disorder, impedes proper recruitment of Orc6 into ORC; biochemical studies reveal that this region of Orc6 associates with a previously uncharacterized domain of Orc3 and is required for ORC function and MCM2-7 loading in vivo. Together, our results suggest that Meier-Gorlin syndrome mutations in Orc6 impair the formation of ORC hexamers, interfering with appropriate ORC functions. DOI:http://dx.doi.org/10.7554/eLife.00882.001.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.00882