DNA replication in primary hepatocytes without the six-subunit ORC. Elife 2025 Apr 30;13
Date
04/30/2025Pubmed ID
40304571Pubmed Central ID
PMC12043314DOI
10.7554/eLife.102915Abstract
The six-subunit ORC is essential for the initiation of DNA replication in eukaryotes. Cancer cell lines in culture can survive and replicate DNA replication after genetic inactivation of individual ORC subunits, ORC1, ORC2, or ORC5. In primary cells, ORC1 was dispensable in the mouse liver for endo-reduplication, but this could be explained by the ORC1 homolog, CDC6, substituting for ORC1 to restore functional ORC. Here, we have created mice with a conditional deletion of ORC2, which does not have a homolog. Although mouse embryo fibroblasts require ORC2 for proliferation, mouse hepatocytes synthesize DNA in cell culture and endo-reduplicate in vivo without ORC2. Mouse livers endo-reduplicate after simultaneous deletion of ORC1 and ORC2 both during normal development and after partial hepatectomy. Since endo-reduplication initiates DNA synthesis like normal S phase replication these results unequivocally indicate that primary cells, like cancer cell lines, can load MCM2-7 and initiate replication without ORC.
Author List
Przanowska RK, Chen Y, Uchida TO, Shibata E, Hao X, Rueda IS, Jensen K, Przanowski P, Trimboli A, Shibata Y, Leone G, Dutta AAuthor
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCells, Cultured
DNA Replication
Endoreduplication
Hepatocytes
Liver
Mice
Origin Recognition Complex
