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Backbone Flexibility Influences Nucleotide Incorporation by Human Translesion DNA Polymerase ? opposite Intrastrand Cross-Linked DNA.


ABSTRACT: Intrastrand cross-links (IaCL) connecting two purine nucleobases in DNA pose a challenge to high-fidelity replication in the cell. Various repair pathways or polymerase bypass can cope with these lesions. The influence of the phosphodiester linkage between two neighboring 2'-deoxyguanosine (dG) residues attached through the O(6) atoms by an alkylene linker on bypass with human DNA polymerase ? (hPol ?) was explored in vitro. Steady-state kinetics and mass spectrometric analysis of products from nucleotide incorporation revealed that although hPol ? is capable of bypassing the 3'-dG in a mostly error-free fashion, significant misinsertion was observed for the 5'-dG of the IaCL containing a butylene or heptylene linker. The lack of the phosphodiester linkage triggered an important increase in frameshift adduct formation across the 5'-dG by hPol ?, in comparison to the 5'-dG of IaCL DNA containing the phosphodiester group.

SUBMITTER: O'Flaherty DK 

PROVIDER: S-EPMC4889123 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Backbone Flexibility Influences Nucleotide Incorporation by Human Translesion DNA Polymerase η opposite Intrastrand Cross-Linked DNA.

O'Flaherty Derek K DK   Guengerich F Peter FP   Egli Martin M   Wilds Christopher J CJ  

Biochemistry 20151216 51


Intrastrand cross-links (IaCL) connecting two purine nucleobases in DNA pose a challenge to high-fidelity replication in the cell. Various repair pathways or polymerase bypass can cope with these lesions. The influence of the phosphodiester linkage between two neighboring 2'-deoxyguanosine (dG) residues attached through the O(6) atoms by an alkylene linker on bypass with human DNA polymerase η (hPol η) was explored in vitro. Steady-state kinetics and mass spectrometric analysis of products from  ...[more]

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