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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Veröffentlicht in:Molecular cell Jg. 22; H. 3; S. 407
Hauptverfasser: Avkin, Sharon, Sevilya, Ziv, Toube, Leanne, Geacintov, Nicholas, Chaney, Stephen G, Oren, Moshe, Livneh, Zvi
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 05.05.2006
Schlagworte:
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
ISSN:1097-2765
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1097-2765
DOI:10.1016/j.molcel.2006.03.022