Document Detail


Regulation of human DNA polymerase delta in the cellular responses to DNA damage.
MedLine Citation:
PMID:  23047826     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The p12 subunit of polymerase delta (Pol δ) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol δ4 holoenzyme to the heterotrimer, Pol δ3. We review studies that establish that Pol δ3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol δ3 exhibits properties of an "antimutator" polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol δ carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol δ to sites of DNA damage show that Pol δ3 is the primary form of Pol δ associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol δ engaged in DNA repair. We propose a model for the switching of Pol δ with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol δ3. Because of the critical role of Pol δ activity in DNA replication and repair, the formation of Pol δ3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability.
Authors:
Marietta Y W T Lee; Sufang Zhang; Szu Hua Sharon Lin; Jennifer Chea; Xiaoxiao Wang; Christine LeRoy; Agnes Wong; Zhongtao Zhang; Ernest Y C Lee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2012-10-10
Journal Detail:
Title:  Environmental and molecular mutagenesis     Volume:  53     ISSN:  1098-2280     ISO Abbreviation:  Environ. Mol. Mutagen.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-08     Completed Date:  2013-01-08     Revised Date:  2013-07-09    
Medline Journal Info:
Nlm Unique ID:  8800109     Medline TA:  Environ Mol Mutagen     Country:  United States    
Other Details:
Languages:  eng     Pagination:  683-98     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. marietta_lee@NYMC.edu
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MeSH Terms
Descriptor/Qualifier:
Alkylating Agents / pharmacology
DNA Damage*
DNA Polymerase III / metabolism*
DNA Replication
Humans
Phosphorylation
Ultraviolet Rays
Grant Support
ID/Acronym/Agency:
ES14737/ES/NIEHS NIH HHS; GM31973/GM/NIGMS NIH HHS; R01 ES014737/ES/NIEHS NIH HHS; R01 GM031973/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Alkylating Agents; EC 2.7.7.-/DNA Polymerase III

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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