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Lookup NU author(s): Dr Irina Neganova, Dr Stuart Atkinson, Dr Joao Passos, Professor Thomas von Zglinicki, Professor Lyle Armstrong, Professor Majlinda LakoORCiD
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A precise understanding of mechanisms used by human embryonic stem cells (hESCs) to maintain genomic integrity is very important for their potential clinical applications. The G1 checkpoint serves to protect genomic integrity and prevents cells with damaged DNA from entering S-phase. Previously, we have shown that downregulation of cyclin-dependent kinase 2 (CDK2) in hESC causes G1 arrest, loss of pluripotency, upregulation of cell cycle inhibitors p21 and p27 and differentiation toward extraembryonic lineages. In this study, we investigate in detail the role of CDK2 in cellular processes, which are crucial to the maintenance of genomic stability in hESC such as G1 checkpoint activation, DNA repair, and apoptosis. Our results suggest that downregulation of CDK2 triggers the G1 checkpoint through the activation of the ATM-CHK2-p53-p21 pathway. Downregulation of CDK2 is able to induce sustained DNA damage and to elicit the DNA damage response (DDR) as evidenced by the formation of distinct gamma-H2.AX and RAD52-BRCA1 foci in hESC nuclei. CDK2 downregulation causes high apoptosis at the early time points; however, this is gradually decreased overtime as the DDR is initiated. Our mass spectrometry analysis suggest that CDK2 does interact with a large number of proteins that are involved in key cellular processes such as DNA replication, cell cycle progression, DNA repair, chromatin modeling, thus, suggesting a crucial role for CDK2 in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in hESC. STEM CELLS 2011; 29: 651-659
Author(s): Neganova I, Vilella F, Atkinson SP, Lloret M, Passos JF, von Zglinicki T, O'Connor JE, Burks D, Jones R, Armstrong L, Lako M
Publication type: Article
Publication status: Published
Journal: Stem Cells
Year: 2011
Volume: 29
Issue: 4
Pages: 651-659
Print publication date: 05/04/2011
ISSN (print): 1066-5099
ISSN (electronic): 1549-4918
Publisher: AlphaMed Press, Inc.
URL: http://dx.doi.org/10.1002/stem.620
DOI: 10.1002/stem.620
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