4DL3

Human DNA polymerase eta inserting dCMPNPP opposite GG template (GG0b).

Summary for 4DL3

• Entry DOI: 10.2210/pdb4dl3/pdb
• Related: 3MR2 3MR3 3MR5 3MR6 3Si8 4DL2 4DL4 4DL5 4DL6 4DL7
• Descriptor: DNA polymerase eta, DNA (5'-D(*TP*AP*CP*GP*GP*TP*CP*AP*CP*AP*CP*T)-3'), DNA (5'-D(*TP*AP*GP*TP*GP*TP*GP*AP*C)-3'), ... (7 entities in total)
• Functional Keywords: cisplatin, chemoresistence, translesion synthesis, human dna polymerse eta, kinetics, molecular splint, inhibition, dna distorsion, second tls polymerase, nucleotidyl transfer reaction, pcna, nucleus, transferase-dna-inhibitor complex, transferase/dna/inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q9Y253
• Total number of polymer chains: 3
• Total formula weight: 55801.99

Authors

Zhao, Y.,Biertumpfel, C.,Gregory, M.,Hua, Y.,Hanaoka, F.,Yang, W. (deposition date: 2012-02-05, release date: 2012-05-09, Last modification date: 2023-09-13)

Primary citation

Zhao, Y.,Biertumpfel, C.,Gregory, M.T.,Hua, Y.J.,Hanaoka, F.,Yang, W.
Structural Basis for Chemoresistance to Cisplatin Mediated by DNA Polymerase eta
Proc.Natl.Acad.Sci.USA, 109:7269-7274, 2012

PubMed Abstract: Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase η (hPol η). Here, we report crystal structures of hPol η complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol η is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol η differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol η undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol η is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol η is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance.

PubMed: 22529383
DOI: 10.1073/pnas.1202681109

Experimental method

X-RAY DIFFRACTION (2.1 Å)