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Nucleic Acids Res. May 1, 2009; 37 (9): 2854-66.

Proofreading exonuclease activity of human DNA polymerase delta and its effects on lesion-bypass DNA synthesis.

Fazlieva R , Spittle CS , Morrissey D , Hayashi H , Yan H , Matsumoto Y .

Replicative DNA polymerases possess 3'' --> 5'' exonuclease activity to reduce misincorporation of incorrect nucleotides by proofreading during replication. To examine if this proofreading activity modulates DNA synthesis of damaged templates, we constructed a series of recombinant human DNA polymerase delta (Pol delta) in which one or two of the three conserved Asp residues in the exonuclease domain are mutated, and compared their properties with that of the wild-type enzyme. While all the mutant enzymes lost more than 95% exonuclease activity and severely decreased the proofreading activity than the wild-type, the bypass efficiency of damaged templates was varied: two mutant enzymes, D515V and D402A/D515A, gave higher bypass efficiencies on templates containing an abasic site, but another mutant, D316N/D515A, showed a lower bypass efficiency than the wild-type. All the enzymes including the wild-type inserted an adenine opposite the abasic site, whereas these enzymes inserted cytosine and adenine opposite an 8-oxoguanine with a ratio of 6:4. These results indicate that the exonuclease activity of human Pol delta modulates its intrinsic bypass efficiency on the damaged template, but does not affect the choice of nucleotide to be inserted.

PubMed ID: 19282447
PMC ID: PMC2685094
Article link: Nucleic Acids Res.
Grant support: CA06315 NCI NIH HHS , CA06927 NCI NIH HHS , CA092584 NCI NIH HHS

Genes referenced: pcna slc19a1

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Abdus Sattar, 1997, Pubmed[+]

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