p53 and p21 regulate error-prone DNA repair to yield a lower mutation load
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 pro...
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| Published in: | Molecular cell Vol. 22; no. 3; p. 407 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
05.05.2006
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| ISSN: | 1097-2765 |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Chaney, Stephen G Sevilya, Ziv Oren, Moshe Livneh, Zvi Geacintov, Nicholas Avkin, Sharon Toube, Leanne |
| Author_xml | – sequence: 1 givenname: Sharon surname: Avkin fullname: Avkin, Sharon organization: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel – sequence: 2 givenname: Ziv surname: Sevilya fullname: Sevilya, Ziv – sequence: 3 givenname: Leanne surname: Toube fullname: Toube, Leanne – sequence: 4 givenname: Nicholas surname: Geacintov fullname: Geacintov, Nicholas – sequence: 5 givenname: Stephen G surname: Chaney fullname: Chaney, Stephen G – sequence: 6 givenname: Moshe surname: Oren fullname: Oren, Moshe – sequence: 7 givenname: Zvi surname: Livneh fullname: Livneh, Zvi |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16678112$$D View this record in MEDLINE/PubMed |
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| Snippet | Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence... |
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| SubjectTerms | Animals Cyclin-Dependent Kinase Inhibitor p21 - deficiency Cyclin-Dependent Kinase Inhibitor p21 - metabolism DNA - biosynthesis DNA Repair - genetics Gene Expression Regulation, Neoplastic Humans Mice Mice, Knockout Mutagenesis - genetics Mutation - genetics Proliferating Cell Nuclear Antigen - chemistry Proliferating Cell Nuclear Antigen - metabolism Protein Binding Protein Structure, Tertiary Tumor Suppressor Protein p53 - deficiency Tumor Suppressor Protein p53 - metabolism Ubiquitin - metabolism Ultraviolet Rays |
| Title | p53 and p21 regulate error-prone DNA repair to yield a lower mutation load |
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