Re: In8 On the importance of DNA-protein crosslinks

From: Dietrich Averbeck
Date: 12/13/97
Time: 4:46:42 PM
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Thank you very much for your kind comment and for your question. It is true that the DNA-protein crosslink story is an intriguing one. As far as I remember, we tried once together with DR. Enrico Cundari with alkaline step elution techniques to detect DNA-protein cross-links after 8-MOP plus UVA treatment in yeast. And indeed, we found some evidence for their presence, however, we did not follow up this work. Furthermore, I believe that Dr. N. Magana-Schwencke tried 15 years ago with gradients to get evidence for UV and especially formaldehyde induced DNA-protein crosslinks. However,although the work with formaldehyde was followed up and published the UV induced DNA-protein cross-links in yeast were not much further explored. Maybe this was due to the fact that Dr. Peak convincingly showed that UV-induced DNA-protein crosslinks were wavelength dependent and they appeared to disappear quite quickly after post-irradiation incubation. With your poster P4 you are bringing up a very interesting question on the importance of different kinds of DNA-protein crosslinks. Indeed, it appears to be of great importance to look at the chemical structure of these DNA-protein crosslinks. Surely, those induced by the photosensitizing furoquinolines that you are using these lÚsions have a striking effect on cell killing. It is easy to imagine that depending on the type of crosslink formed between DNA bases and surrounding proteins that they will constitute more or less effective lesions in blocking cell cycle progression. Is it really so that one can say that the DNA-protein crosslinks of the compounds 8-MOP, FQ and HFQ would have equal effectiveness? I think your work and your comment are of great general interest because DNA-crosslinks should be involved in the unfolding of chromatin necessary for repair enzymes to get access to DNA. If the damaged region of DNA is covalently linked to proteins than this accessibility is certainly a big obstacle for DNA repair to operate. Well, I guess that following your work we will confronted with a lot of more work finding out how DNA-protein crosslinks will interfere with normal DNA replication and repair after photosensitization. With many thanks again for your comment and lookin g forward to more work on this very intriguing subject, kind regards, Dietrich

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