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

Bleichert, Franziska; Balasov, Maxim; Chesnokov, Igor; Nogales, Eva; Botchan, Michael R.; Berger, James M.

doi:10.7554/elife.00882

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

Journal Article · Tue Oct 08 00:00:00 EDT 2013 · eLife

DOI:https://doi.org/10.7554/elife.00882· OSTI ID:1628799

Bleichert, Franziska ^[1]; Balasov, Maxim ^[2]; Chesnokov, Igor ^[2]; Nogales, Eva ^[3]; Botchan, Michael R. ^[4]; Berger, James M. ^[4]

Univ. of California, Berkeley, CA (United States). Miller Inst. for Basic Research in Science; Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; DOE/OSTI
Univ. of Alabama, Birmingham, AL (United States). School of Medicine. Dept. of Biochemistry and Molecular Genetics
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Inst.
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1628799

Journal Information:: eLife, Journal Name: eLife Vol. 2; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Structure of the origin recognition complex bound to DNA replication origin Li, Ningning; Lam, Wai Hei; Zhai, Yuanliang Nature, Vol. 559, Issue 7713 https://doi.org/10.1038/s41586-018-0293-x	journal	July 2018
From structure to mechanism—understanding initiation of DNA replication Riera, Alberto; Barbon, Marta; Noguchi, Yasunori Genes & Development, Vol. 31, Issue 11 https://doi.org/10.1101/gad.298232.117	journal	June 2017
Tissue-Specific DNA Replication Defects in Drosophila melanogaster Caused by a Meier-Gorlin Syndrome Mutation in Orc4 McDaniel, Stephen L.; Hollatz, Allison J.; Branstad, Anna M. Genetics, Vol. 214, Issue 2 https://doi.org/10.1534/genetics.119.302938	journal	February 2020

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