Article: article from journal or magazin.
How adeno-associated virus Rep78 protein arrests cells completely in S phase.
Proceedings of the National Academy of Sciences of the United States of America
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Adeno-associated virus Rep78 protein has antiproliferative effects on cells. It inhibits cell cycle progression, and, in particular, Rep78 induces a complete arrest within S phase, a response rarely seen after cell DNA damage. We examined how Rep78 achieves such an efficient S phase block. Rep78 inhibits Cdc25A activity by a novel means in which binding between the two proteins stabilizes Cdc25A, thus increasing its abundance, while at the same time preventing access to its substrates cyclin-dependent kinase (Cdk) 2 and Cdk1. This effect alone does not induce a complete S phase block. In addition, Rep78, as well as Rep68, produces nicks in the cellular chromatin, inducing a DNA damage response mediated by ataxia telangiectasia mutated (ATM) leading to G(1) and G(2) blocks. Mutational analysis shows that the zinc finger domain and nuclease activity of Rep78 are both required for the S phase block. The results suggest that a true S phase block cannot be achieved through a single pathway, and that adeno-associated virus Rep78 protein arrests cells within S phase by interfering with two pathways that would normally lead to an S phase slow-down.
CDC2 Protein Kinase/metabolism, CDC2-CDC28 Kinases/metabolism, Cell Cycle Proteins/metabolism, Cell Proliferation, Chromatin/metabolism, Cyclin-Dependent Kinase 2, DNA Damage, DNA-Binding Proteins/genetics, DNA-Binding Proteins/metabolism, Hela Cells, Humans, Protein-Serine-Threonine Kinases/metabolism, S Phase/genetics, S Phase/physiology, Transfection, Tumor Suppressor Proteins/metabolism, Viral Proteins/genetics, Viral Proteins/metabolism, cdc25 Phosphatases/metabolism
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