2R8K

Structure of the Eukaryotic DNA Polymerase eta in complex with 1,2-d(GpG)-cisplatin containing DNA

Summary for 2R8K

• Entry DOI: 10.2210/pdb2r8k/pdb
• Related: 1JIH 2R8J
• Descriptor: 5'-D(*DGP*DTP*DGP*DGP*DTP*DGP*DAP*DGP*DC)-3', 5'-D(P*DGP*DGP*DCP*DTP*DCP*DAP*DCP*DCP*DAP*DC)-3', DNA polymerase eta, ... (6 entities in total)
• Functional Keywords: protein-cisplatin-dna-dntp complex, replication, transferase-dna complex, transferase/dna
• Biological source: Saccharomyces cerevisiae (baker's yeast)
• Cellular location: Nucleus: Q04049
• Total number of polymer chains: 6
• Total formula weight: 138581.96

Authors

Carell, T.,Alt, A.,Lammens, K. (deposition date: 2007-09-11, release date: 2007-12-11, Last modification date: 2023-08-30)

Primary citation

Alt, A.,Lammens, K.,Chiocchini, C.,Lammens, A.,Pieck, J.C.,Kuch, D.,Hopfner, K.P.,Carell, T.
Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta
Science, 318:967-970, 2007

PubMed Abstract: DNA polymerase eta (Pol eta) is a eukaryotic lesion bypass polymerase that helps organisms to survive exposure to ultraviolet (UV) radiation, and tumor cells to gain resistance against cisplatin-based chemotherapy. It allows cells to replicate across cross-link lesions such as 1,2-d(GpG) cisplatin adducts (Pt-GG) and UV-induced cis-syn thymine dimers. We present structural and biochemical analysis of how Pol eta copies Pt-GG-containing DNA. The damaged DNA is bound in an open DNA binding rim. Nucleotidyl transfer requires the DNA to rotate into an active conformation, driven by hydrogen bonding of the templating base to the dNTP. For the 3'dG of the Pt-GG, this step is accomplished by a Watson-Crick base pair to dCTP and is biochemically efficient and accurate. In contrast, bypass of the 5'dG of the Pt-GG is less efficient and promiscuous for dCTP and dATP as a result of the presence of the rigid Pt cross-link. Our analysis reveals the set of structural features that enable Pol eta to replicate across strongly distorting DNA lesions.

PubMed: 17991862
DOI: 10.1126/science.1148242

Experimental method

X-RAY DIFFRACTION (3.3 Å)