Endoreduplication of the mouse genome in the absence of ORC1
- Takayuki Okano-Uchida1,
- Lindsey N. Kent1,
- Madhu M. Ouseph2,3,4,
- Britney McCarty2,3,4,
- Jeffrey J. Frank2,3,4,
- Raleigh Kladney2,3,4,
- Maria C. Cuitino1,
- John C. Thompson2,3,4,
- Vincenzo Coppola2,3,4,
- Maki Asano2,3,5 and
- Gustavo Leone1
- 1Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA;
- 2Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA;
- 3Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA;
- 4Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA;
- 5Department of Molecular Cellular and Biochemistry, Ohio State University, Columbus, Ohio 43210, USA
- Corresponding author: leoneg{at}musc.edu
Abstract
The largest subunit of the origin recognition complex (ORC1) is essential for assembly of the prereplicative complex, firing of DNA replication origins, and faithful duplication of the genome. Here, we generated knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. Global or tissue-specific ablation of ORC1 function in mouse embryo fibroblasts and fetal and adult diploid tissues blocked DNA replication, cell lineage expansion, and organ development. Remarkably, ORC1 ablation in extraembryonic trophoblasts and hepatocytes, two polyploid cell types in mice, failed to impede genome endoreduplication and organ development and function. Thus, ORC1 in mice is essential for mitotic cell divisions but dispensable for endoreduplication. We propose that DNA replication of mammalian polyploid genomes uses a distinct ORC1-independent mechanism.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.311910.118.
- Received January 25, 2018.
- Accepted May 9, 2018.
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