Reports

Bypass of DNA Lesions Generated During Anticancer Treatment with Cisplatin by DNA Polymerase

Aaron Alt,^1* Katja Lammens,^1,2* Claudia Chiocchini,¹ Alfred Lammens,^1,2 J. Carsten Pieck,¹ David Kuch,¹ Karl-Peter Hopfner,^1,2 Thomas Carell¹

DNA polymerase (Pol ) 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 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 to replicate across strongly distorting DNA lesions.

¹ Munich Center for Integrated Protein Science (CiPS^M), Ludwig Maximilians University, D-81377 Munich, Germany.
² Gene Center at the Department of Chemistry and Biochemistry, Ludwig Maximilians University, D-81377 Munich, Germany.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: hopfner{at}lmb.uni-muenchen.de (K.-P.H.); thomas.carell{at}cup.uni-muenchen.de (T.C.)

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Critical amino acids in human DNA polymerases {eta} and {kappa} involved in erroneous incorporation of oxidized nucleotides.

A. Katafuchi, A. Sassa, N. Niimi, P. Gruz, H. Fujimoto, C. Masutani, F. Hanaoka, T. Ohta, and T. Nohmi (2009)
Nucleic Acids Res.
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Structural and Functional Elucidation of the Mechanism Promoting Error-prone Synthesis by Human DNA Polymerase {kappa} Opposite the 7,8-Dihydro-8-oxo-2'-deoxyguanosine Adduct.

A. Irimia, R. L. Eoff, F. P. Guengerich, and M. Egli (2009)
J. Biol. Chem. 284, 22467-22480
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Conformational Changes during Nucleotide Selection by Sulfolobus solfataricus DNA Polymerase Dpo4.

R. L. Eoff, R. Sanchez-Ponce, and F. P. Guengerich (2009)
J. Biol. Chem. 284, 21090-21099
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Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance.

L. S. Waters, B. K. Minesinger, M. E. Wiltrout, S. D'Souza, R. V. Woodruff, and G. C. Walker (2009)
Microbiol. Mol. Biol. Rev. 73, 134-154
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Polymerase {eta} mRNA Expression Predicts Survival of Non-Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

P. Ceppi, S. Novello, A. Cambieri, M. Longo, V. Monica, M. Lo Iacono, M. Giaj-Levra, S. Saviozzi, M. Volante, M. Papotti, et al. (2009)
Clin. Cancer Res. 15, 1039-1045
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Lesion Bypass of N2-Ethylguanine by Human DNA Polymerase {iota}.

M. G. Pence, P. Blans, C. N. Zink, T. Hollis, J. C. Fishbein, and F. W. Perrino (2009)
J. Biol. Chem. 284, 1732-1740
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The N-clasp of human DNA polymerase {kappa} promotes blockage or error-free bypass of adenine- or guanine-benzo[a]pyrenyl lesions.

L. Jia, N. E. Geacintov, and S. Broyde (2008)
Nucleic Acids Res. 36, 6571-6584
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Mechanism of double-base lesion bypass catalyzed by a Y-family DNA polymerase.

J. A. Brown, S. A. Newmister, K. A. Fiala, and Z. Suo (2008)
Nucleic Acids Res. 36, 3867-3878
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Newer Cytotoxic Agents: Attacking Cancer Broadly.

B. A. Teicher (2008)
Clin. Cancer Res. 14, 1610-1617
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