Abstract
BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2−/−) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2−/− mESCs following gamma irradiation. In addition, Babam2−/− mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2−/− mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.
Highlights
The BRISC and BRCA1-A complex member 2 (Babam2) gene, known as BRE, encodes a highly conserved protein in mammals
We examined the consequence of high pp53 expressions in Babam2−/− mouse embryonic stem cells (mESCs) and found they inhibited NANOG expression but not OCT4 and SOX2
Pluripotent mESCs are known to have unlimited we examined the activities of this enzyme in Babam2 and WT mESCs, 1–5 days post-irradiation self-renewalAlkaline capability without entering senescence, demonstrated loss of phosphatase staining revealedwethat
Summary
The BRISC and BRCA1-A complex member 2 (Babam2) gene, known as BRE, encodes a highly conserved protein in mammals. It has been reported that a correctly regulated cell cycle progression is essential for mESCs to maintain their pluripotency and genomic stability, especially following DNA damage [13]. CDK2 is essential for both promoting rapid G1/S cell cycle progression and maintaining the developmental pluripotency of mESCs. p53 is capable of binding to the Nanog promoter to repress Nanog transcription [18]. The increased p53 expression seen following DNA damage can potentially induce mESCs to differentiate by Nanog-targeted inhibition [18]. CDC25A is involved in the activation of CDK2 and facilitates G1/S transition [23] These studies indicate that p53 can repress G1 cell cycle progression. We investigated the role of Babam in cell cycle regulation and pluripotency in mESCs after DNA damage.
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