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PDBsum entry 3m9n
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Transferase/DNA
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PDB id
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3m9n
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References listed in PDB file
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Key reference
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Title
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Structural insight into dynamic bypass of the major cisplatin-Dna adduct by y-Family polymerase dpo4.
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Authors
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J.H.Wong,
J.A.Brown,
Z.Suo,
P.Blum,
T.Nohmi,
H.Ling.
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Ref.
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Embo J, 2010,
29,
2059-2069.
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PubMed id
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Abstract
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Y-family DNA polymerases bypass Pt-GG, the cisplatin-DNA double-base lesion,
contributing to the cisplatin resistance in tumour cells. To reveal the
mechanism, we determined three structures of the Y-family DNA polymerase, Dpo4,
in complex with Pt-GG DNA. The crystallographic snapshots show three stages of
lesion bypass: the nucleotide insertions opposite the 3'G (first insertion) and
5'G (second insertion) of Pt-GG, and the primer extension beyond the lesion
site. We observed a dynamic process, in which the lesion was converted from an
open and angular conformation at the first insertion to a depressed and nearly
parallel conformation at the subsequent reaction stages to fit into the active
site of Dpo4. The DNA translocation-coupled conformational change may account
for additional inhibition on the second insertion reaction. The structures
illustrate that Pt-GG disturbs the replicating base pair in the active site,
which reduces the catalytic efficiency and fidelity. The in vivo relevance of
Dpo4-mediated Pt-GG bypass was addressed by a dpo-4 knockout strain of
Sulfolobus solfataricus, which exhibits enhanced sensitivity to cisplatin and
proteomic alterations consistent with genomic stress.
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