Keeping mammalian mutation load in check: regulation of the activity of error-prone DNA polymerases by p53 and p21.
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.
Livneh
Zvi
Z
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. zvi.livneh@weizmann.ac.il
D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D008957:Models, Genetic; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D004247:DNA; D004259:DNA-Directed DNA Polymerase