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PCNA trimer stability and its impact on mutagenesis
Author(s) -
Washington M. Todd,
Dieckman Lynne,
Kondratick Christine
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb90
Subject(s) - dna polymerase , processivity , proliferating cell nuclear antigen , mutagenesis , dna clamp , trimer , dna replication , polymerase , dna , dna polymerase ii , replication factor c , mutant , biology , microbiology and biotechnology , chemistry , biochemistry , eukaryotic dna replication , gene , polymerase chain reaction , reverse transcriptase , dimer , organic chemistry
Mutagenesis drives carcinogenesis by activating proto‐oncogenes and inactivating tumor suppressor genes. To develop novel strategies to reduce mutagenesis, we are studying several PCNA mutant proteins that are unable to support translesion synthesis, the error‐prone replication of damaged DNA. PCNA is a key replication accessory factor that forms a trimer that encircles DNA and confers high processivity to classical DNA polymerases. The X‐ray crystal structures of these PCNA mutant proteins show that they have disruptions in the anti‐parallel beta sheet constituting the PCNA subunit interface. As a result, these mutant proteins have moderately reduced trimer stabilities. Moreover, kinetic studies with both classical and non‐classical DNA polymerases in the presence of these mutant PCNA proteins show that the ability of both types of DNA polymerases to carry out translesion synthesis is impaired. This has lead us to a new model by which decreased PCNA trimer stability prevents the replicative bypass of DNA lesions by all DNA polymerases. This suggests that one may be able to reduce mutagenesis by decreasing PCNA trimer stability. The project described was supported by Award Number GM081433 from the National Institute of General Medical Sciences to M.T.W.