Content area
Full Text
About the Authors:
Joseph C. Sanchez
Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
Affiliations Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States of America, Department of Genome Sciences, University of Washington, Seattle, WA, United States of America
Elizabeth X. Kwan
Roles Software
Affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, United States of America
Thomas J. Pohl
Roles Conceptualization, Resources, Validation
Affiliations Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States of America, Department of Genome Sciences, University of Washington, Seattle, WA, United States of America
ORCID http://orcid.org/0000-0002-8182-3249
Haley M. Amemiya
Roles Resources, Validation
Affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, United States of America
ORCID http://orcid.org/0000-0002-2610-4436
M. K. Raghuraman
Roles Conceptualization, Funding acquisition, Methodology, Supervision, Writing - original draft, Writing - review & editing
Affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, United States of America
Bonita J. Brewer
Roles Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
* E-mail: [email protected]
Affiliations Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States of America, Department of Genome Sciences, University of Washington, Seattle, WA, United States of AmericaAbstract
A form of dwarfism known as Meier-Gorlin syndrome (MGS) is caused by recessive mutations in one of six different genes (ORC1, ORC4, ORC6, CDC6, CDT1, and MCM5). These genes encode components of the pre-replication complex, which assembles at origins of replication prior to S phase. Also, variants in two additional replication initiation genes have joined the list of causative mutations for MGS (Geminin and CDC45). The identity of the causative MGS genetic variants strongly suggests that some aspect of replication is amiss in MGS patients; however, little evidence has been obtained regarding what aspect of chromosome replication is faulty. Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C). We find that yeast cells with the orc4Y232C allele have...