p53 and p21 Regulate Error-Prone DNA Repair to Yield a Lower Mutation Load

Sharon Avkin; Ziv Sevilya; Leanne Toube; Nicholas Geacintov; Stephen G. Chaney; Moshe Oren; Zvi Livneh

doi:10.1016/j.molcel.2006.03.022

p53 and p21 Regulate Error-Prone DNA Repair to Yield a Lower Mutation Load

Sharon Avkin, Ziv Sevilya, Leanne Toube, Nicholas Geacintov, Stephen G. Chaney, Moshe Oren, Zvi Livneh

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p21 to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p21. Loss of this regulation by inactivation of p53 or p21 causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability.

Original language	English (US)
Pages (from-to)	407-413
Number of pages	7
Journal	Molecular Cell
Volume	22
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2006.03.022
State	Published - May 5 2006

Keywords

CELLCYCLE
DNA

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2006.03.022

Cite this

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title = "p53 and p21 Regulate Error-Prone DNA Repair to Yield a Lower Mutation Load",

abstract = "Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p21 to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p21. Loss of this regulation by inactivation of p53 or p21 causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability.",

keywords = "CELLCYCLE, DNA",

author = "Sharon Avkin and Ziv Sevilya and Leanne Toube and Nicholas Geacintov and Chaney, {Stephen G.} and Moshe Oren and Zvi Livneh",

note = "Funding Information: We thank Bert Vogelstein (The Johns Hopkins University Medical Institutions, Baltimore, MD), Arun Fotedar (Sidney Kimmel Cancer Center, San Diego, CA), and Rati Fotedar (Institut de Biologie Structurale, Grenoble, France) for the p21 clones, Aaron Ciechanover (Technion, Haifa, Israel) for help on ubiquitination, and Edna Schechtman (Ben Gurion University, Beer Sheva, Israel) for help in statistical analysis. Z.L. is the incumbent of the Maxwell Ellis Chair for Biomedical Research. This work was supported by a grant from the Flight Attendant Medical Institute, Florida, USA to Z.L. and M.O., by grants no. 78/00 and 564/04 from the Israel Science Foundation, by a grant from the M.D. Moross Institute for Cancer Research at the Weizmann Institute of Science to Z.L., and by grant CA 099194 from the National Institutes of Health to N.G. ",

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AU - Avkin, Sharon

AU - Sevilya, Ziv

AU - Toube, Leanne

AU - Geacintov, Nicholas

AU - Chaney, Stephen G.

AU - Oren, Moshe

AU - Livneh, Zvi

N1 - Funding Information: We thank Bert Vogelstein (The Johns Hopkins University Medical Institutions, Baltimore, MD), Arun Fotedar (Sidney Kimmel Cancer Center, San Diego, CA), and Rati Fotedar (Institut de Biologie Structurale, Grenoble, France) for the p21 clones, Aaron Ciechanover (Technion, Haifa, Israel) for help on ubiquitination, and Edna Schechtman (Ben Gurion University, Beer Sheva, Israel) for help in statistical analysis. Z.L. is the incumbent of the Maxwell Ellis Chair for Biomedical Research. This work was supported by a grant from the Flight Attendant Medical Institute, Florida, USA to Z.L. and M.O., by grants no. 78/00 and 564/04 from the Israel Science Foundation, by a grant from the M.D. Moross Institute for Cancer Research at the Weizmann Institute of Science to Z.L., and by grant CA 099194 from the National Institutes of Health to N.G.

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N2 - Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p21 to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p21. Loss of this regulation by inactivation of p53 or p21 causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability.

AB - Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p21 to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p21. Loss of this regulation by inactivation of p53 or p21 causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability.

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p53 and p21 Regulate Error-Prone DNA Repair to Yield a Lower Mutation Load

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