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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The negative role of cyclin G in ATM-dependent p53 activation
Takao Ohtsuka1, Michael R Jensen, Hyung Gu Kim
1Cancer Biology Program, Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Cyclin G is one of the earliest p53 target genes to be identified, but its function in the p53 pathway has been elusive. Although the precise mechanisms of cyclin G in this novel network have not been explored, recent studies have demonstrated that cyclin G is a key regulator of the p53-Mdm2 network. Here we present evidence that cyclin G-mediated p53 regulation is dependent upon the status of ataxia-telangiectasia mutated (ATM) protein, which activates p53 in response to DNA damage. Abrogation of cyclin G enhances p53 accumulation and phosphorylation of p53 at the Ser-15 residue, resulting in cell cycle arrest. Ectopically expressed cyclin G significantly reduces the steady-state levels of p53 as well as that of phosphorylated p53 at Ser-15 after DNA damage in normal human dermal fibroblasts containing normal ATM. However, cyclin G does not cause similar reductions in p53 levels in ATM-mutated cells. We also show that translocation of cyclin G to the nucleus requires functional ATM. Thus, our findings identify a new role of cyclin G in ATM-dependent p53 regulation and in cell cycle regulation during DNA damage.
Insights
Cyclin G regulates the p53 pathway by depending on ATM protein status. Loss of cyclin G increases p53 levels and cell cycle arrest, while its presence reduces p53 after DNA damage in an ATM-dependent manner.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cyclin G is an early p53 target gene with an unclear role in the p53 pathway.
- Recent research suggests cyclin G is a key regulator of the p53-Mdm2 network.
Purpose of the Study:
- To investigate the role of cyclin G in p53 regulation.
- To determine the dependence of cyclin G's function on ataxia-telangiectasia mutated (ATM) protein status.
Main Methods:
- Studied p53 accumulation and phosphorylation at Ser-15 in response to DNA damage.
- Examined the effect of cyclin G abrogation and ectopic expression.
- Assessed cyclin G nuclear translocation in ATM-proficient and ATM-mutated cells.
Main Results:
- Abrogation of cyclin G enhanced p53 accumulation and phosphorylation, leading to cell cycle arrest.
- Ectopic cyclin G reduced p53 levels post-DNA damage in ATM-normal cells but not in ATM-mutated cells.
- Functional ATM was required for cyclin G's nuclear translocation.
Conclusions:
- Cyclin G plays a novel role in ATM-dependent p53 regulation.
- Cyclin G influences cell cycle regulation during DNA damage response through an ATM-dependent mechanism.
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