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Resistent tumors in chemotherapy

Munich, 11/15/2007

Cisplatin is used in chemotherapy to treat a variety of cancers. This drug binds stably to DNA and causes crosslink lesions which block the molecule’s replication. Cells need a second copy of their DNA for cell division. Blocking replication kills rapidly reproducing cells like cancer. But tumors can become resistant to cisplatin. One mechanism involves DNA polymerase “eta”. This enzyme allows cells to replicate across crosslink lesions. In the journal Science, a research team at Ludwig-Maximilians-Universität (LMU) München presents a structural and biochemical analysis of how DNA polymerase "eta" copies DNA that contains these cisplatin adducts – and thereby creates resistance to cisplatin. “Our results reveal the set of structural features that enable the enzyme to replicate across strongly distorting DNA lesions,” says Professor Karl-Peter Hopfner, one of the project leaders. “This information may help to develop new cisplatin derivatives able to escape replication across lesions in order to overcome tumor resistance in cisplatin chemotherapy.”

DNA polymerases synthesize a second set of DNA before cell division occurs. Polymerases "delta" and "epsilon" for example, copy the molecule in a highly precise and efficient way. If they reach a lesion along the DNA strand, further replication will be blocked. Unless the mutation can be fixed, the cell will die – a process that is used in chemotherapy for the patient’s benefit. Cisplatin is a drug that creates crosslinks in DNA by complexing two adjacent bases. The four bases thymine, adenine, guanine, and cytosine are the DNA’s building blocks. Cells are not completely defenceless though: They can correct these lesions to some extent, but in chemotherapy the number of cisplatin-induced crosslinks exceeds a cell’s capacity for repair; unless, of course, a tumor cell becomes resistant. DNA polymerase "eta" is one of the 15 known human DNA polymerases. It fulfils an important function when cells are damaged by another type of crosslink: UV radiation in sunlight can crosslink two adjacent thymines in DNA. DNA polymerases are typically blocked by this obstacle or generate mutations, with the one exception being DNA polymerase ""eta". In sunlight, these crosslinks often cannot be repaired quickly enough. The result: DNA is copied incorrectly – which can lead to cancer – or its synthesis is blocked causing cells to die.

DNA polymerase "eta" allows cells to divide in an almost normal way, and attend to the DNA lesions later. Patients with a defect in the POLH gene which codes for DNA polymerase "eta" suffer from one variant of the disease Xeroderma Pigmentosum, in which exposure to sunlight invariably leads to melanoma. “We crystallographically analyzed different complexes of cisplatin bound to DNA with crosslinks,” says Professor Thomas Carell, a second project leader. “This data together with biochemical results provide a step-by-step picture of the lesion bypass process.” The difference lies in the enzyme’s active center, which is much more open and therefore less specific: DNA polymerase "eta" is able to hold the contorted DNA molecule and read across the lesion. The crosslink consists of two DNA building blocks. As the new data show, the first one of these will be read correctly, the second one with less precision. This is because the second base is held at a right angle, which makes it hard to read. “It’s even possible that mistakes happen at this stage of replication, which in turn will increase the tumor cells’ mutation rate and accelerate the development of the disease,” says Hopfner. “All our results are especially important for medical research since it might be possible to develop another cisplatin with slight changes in its structure that prevent copying by DNA polymerase "eta".”

Publication:
“Bypass of DNA Lesions Generated During Anticancer Treatment with Cisplatin by DNA Polymerase "eta"”
Aaron Alt, Katja Lammens, Claudia Chiocchini, Alfred Lammens, J. Carsten Pieck, David Kuch, Karl-Peter Hopfner, and Thomas Carell
Science, November 9, 2007

Contact:
Professor Dr. Thomas Carell
Department of Chemistry and Biochemistry at LMU
Tel.: +49-89-2180-77750
Fax: +49-89-2180-77756
E-mail: Thomas.Carell@cup.uni-muenchen.de

Professor Dr. Karl-Peter Hopfner
Gene Center at LMU
Tel.: +49-89-2180-76953
Fax: +49-89-2180-76999
E-mail: hopfner@lmb.uni-muenchen.de