Keeping mammalian mutation load in check: regulation of the activity of error-prone DNA polymerases by p53 and p21
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Published on: August 4, 2019
1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. zvi.livneh@weizmann.ac.il
Abstract:
To overcome DNA lesions that block replication the cell employs translesion DNA synthesis (TLS) polymerases, a group of low fidelity DNA polymerases that have the capacity to bypass a wide range of DNA lesions. This TLS process is also termed error-prone repair, due to its inherent mutagenic nature. We have recently shown that the tumor suppressor p53 and the cell cycle inhibitor p21 are global regulators of TLS. When these proteins are missing or nonfunctional, TLS gets out of control: its extent increases to very high levels, and its fidelity decreases, causing an overall increase in mutation load. This may be explained by the loss of selectivity in the bypass of specific DNA lesions by their cognate specialized polymerases, such that lesion bypass continues to a maximum, regardless of the price paid in increased mutations. The p53 and p21 proteins are also required for efficient UV light-induced monoubiquitination of PCNA, which is consistent with a model in which this modification of PCNA is necessary but not sufficient for the normal activity of TLS. This regulation suggests that TLS evolved in mammals as a system that balances gain in survival with a tolerable mutational cost, and that disturbing this balance causes a potentially harmful increase in mutations, which might play a role in carcinogenesis.
Insights
Tumor suppressor proteins p53 and p21 normally control translesion DNA synthesis (TLS), a DNA repair process. Loss of these proteins leads to uncontrolled, error-prone TLS, increasing mutation rates and potentially contributing to cancer.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Translesion DNA synthesis (TLS) utilizes low-fidelity polymerases to bypass DNA lesions, a process crucial for replication survival but inherently mutagenic.
- The tumor suppressor protein p53 and cell cycle inhibitor p21 are identified as key regulators of global TLS activity.
Purpose of the Study:
- To investigate the regulatory role of p53 and p21 in controlling the fidelity and extent of translesion DNA synthesis.
- To elucidate the mechanism by which p53 and p21 regulate TLS, including their interaction with PCNA ubiquitination.
Main Methods:
- The study likely involved experiments assessing TLS activity and fidelity in cells with and without functional p53 and p21.
- Analysis of PCNA monoubiquitination in response to UV irradiation was likely performed.
Main Results:
- Loss or dysfunction of p53 and p21 leads to dysregulated TLS, characterized by increased mutagenic bypass of DNA lesions.
- p53 and p21 are essential for efficient UV-induced PCNA monoubiquitination, a modification linked to TLS regulation.
- This deregulation results in a significantly higher mutation load.
Conclusions:
- p53 and p21 act as critical gatekeepers, balancing DNA replication survival with a tolerable mutation rate during TLS.
- Disruption of this regulatory balance by p53/p21 loss can lead to excessive mutagenesis, potentially promoting carcinogenesis.
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