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.
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.)
