Open AccessGeminin is Essential to Prevent DNA Re‐Replication‐Dependent Apoptosis in Pluripotent Cells, but not in Differentiated Cells
Author(s) -
Huang YiYuan,
Kaneko Kotaro J.,
Pan Haiyan,
DePamphilis Melvin L.
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2092
Subject(s) - biology , microbiology and biotechnology , embryonic stem cell , dna damage , dna replication , dna replication factor cdt1 , cellular differentiation , induced pluripotent stem cell , gene , genetics , dna , control of chromosome duplication
Abstract Geminin is a dual‐function protein unique to multicellular animals with roles in modulating gene expression and preventing DNA re‐replication. Here, we show that geminin is essential at the beginning of mammalian development to prevent DNA re‐replication in pluripotent cells, exemplified by embryonic stem cells, as they undergo self‐renewal and differentiation. Embryonic stem cells, embryonic fibroblasts, and immortalized fibroblasts were characterized before and after geminin was depleted either by gene ablation or siRNA. Depletion of geminin under conditions that promote either self‐renewal or differentiation rapidly induced DNA re‐replication, followed by DNA damage, then a DNA damage response, and finally apoptosis. Once differentiation had occurred, geminin was no longer essential for viability, although it continued to contribute to preventing DNA re‐replication induced DNA damage. No relationship was detected between expression of geminin and genes associated with either pluripotency or differentiation. Thus, the primary role of geminin at the beginning of mammalian development is to prevent DNA re‐replication‐dependent apoptosis, a role previously believed essential only in cancer cells. These results suggest that regulation of gene expression by geminin occurs only after pluripotent cells differentiate into cells in which geminin is not essential for viability. S tem C ells 2015;33:3239–3253