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p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice
Irene M Ward1, Kay Minn, Jan van Deursen
1Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Abstract:
53BP1 is a p53 binding protein of unknown function that binds to the central DNA-binding domain of p53. It relocates to the sites of DNA strand breaks in response to DNA damage and is a putative substrate of the ataxia telangiectasia-mutated (ATM) kinase. To study the biological role of 53BP1, we disrupted the 53BP1 gene in the mouse. We show that, similar to ATM(-/-) mice, 53BP1-deficient mice were growth retarded, immune deficient, radiation sensitive, and cancer prone. 53BP1(-/-) cells show a slight S-phase checkpoint defect and prolonged G(2)/M arrest after treatment with ionizing radiation. Moreover, 53BP1(-/-) cells feature a defective DNA damage response with impaired Chk2 activation. These data indicate that 53BP1 acts downstream of ATM and upstream of Chk2 in the DNA damage response pathway and is involved in tumor suppression.
Insights
The study reveals that the 53BP1 protein is crucial for DNA repair and tumor suppression. Mice lacking 53BP1 exhibit severe developmental, immune, and cancer-related issues, highlighting its essential role in maintaining genomic stability.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- 53BP1 (p53 binding protein 1) is a protein that interacts with p53.
- Its precise function and role in DNA damage response were previously unknown.
- It is implicated as a substrate for the ATM kinase.
Purpose of the Study:
- To elucidate the biological function of 53BP1.
- To investigate the role of 53BP1 in the DNA damage response pathway.
- To determine if 53BP1 is involved in tumor suppression.
Main Methods:
- Gene disruption of 53BP1 in mice (53BP1 knockout).
- Phenotypic analysis of 53BP1-deficient mice.
- Cellular analysis of DNA damage response, including cell cycle checkpoint and kinase activation in 53BP1(-/-) cells.
Main Results:
- 53BP1-deficient mice displayed growth retardation, immunodeficiency, radiation sensitivity, and cancer predisposition, mirroring ATM-deficient mice.
- 53BP1(-/-) cells showed a mild S-phase checkpoint defect and prolonged G(2)/M arrest post-ionizing radiation.
- Impaired Chk2 activation was observed in 53BP1(-/-) cells, indicating a defective DNA damage response.
Conclusions:
- 53BP1 functions downstream of ATM and upstream of Chk2 in the DNA damage response pathway.
- 53BP1 plays a significant role in tumor suppression.
- The findings establish 53BP1 as a critical component of the cellular response to DNA damage and a key player in preventing cancer.