Visual Universitätsmedizin Mainz

Prof. Dr. Bernd Kaina

 

 

 

 

 

 

 

 

CV English (Pdf-file, 98,9 KB)

 

 

 

DNA repair in the cells' protection system

A cell normally has two copies of each gene while germ cells have actually only one copy. Therefore, DNA damage cannot be replaced, as in the case of other cell components, but rather repaired. DNA damage, which has not been repaired, leads to cell death and, ultimately, to mutations in case of cell survival. These mutations have far-reaching consequences for both the cell and organism levels (see Figure). The unrepaired damage to DNA is the starting point for the development of cancer. On a cellular level, DNA repair can be considered the main defence system through which genetic material is protected from harmful exposures.

We analyse the meaning of the different DNA repair pathways in the cells’ protection system with regard to cytotoxicity, genotoxic changes and malignant transformation (cancer) in our projects. We work with cells which show defects in certain DNA repair pathways, or else produce genetic cells as well as in individuals (mice), in which certain repair pathways are strongly expressed or inactivated (knockdown, knockout). In this way, we showed, for instance, that the MGMT repair protein is extremely important for both the cells’ protection system and the organism against alkylating carcinogens. These carcinogens are to be found in food and tobacco smoke. We also showed that a repair system- a mismatch repair- is necessary to convert certain lesions into genotoxic damage. At the same time, this demonstrates that, although DNA repair normally protects, it can also turn out defective and have fatal consequences for the cells.


Christmann M., Tomicic-Christmann M., Roos W., Kaina B. (2003) Mechanisms of human DNA-repair - an update, Toxicology, 193, 3-34


Debiak M., T. Nikolova, Kaina B. (2004) Loss of ATM sensitizes against O6- methylguanine triggered apoptosis, SCEs and chromosomal aberrations, DNA Repair, 3, 359-368


Kaina B. (2005) Chemische Kanzerogenese, Lehrbuchbeitrag in: K. Aktories, U. Förstermann, F. Hofmann und K. Starke, Urban&Fischer Verlag, München, Jena, 9. Auflage, 976-1000


Efferth, T., Kaina B. (2007) Chemical carcinogenesis: genotoxic and non-genotoxic mechanisms. In: H. Greim and R. Snyder(edts), Toxicology and risk assessment: a comprehensive introduction, John Wiley & Sons Ltd., pp. 151-179


Kaina B., Christmann M., Naumann S., Roos W. (2007) MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Repair, 6, 1079-1099

Roos W., Nikolova T., Quiros S., Naumann S., Kiedron O., Zdzienicka M., Kaina B. (2009) BRCA2/XRCC2 dependent HR, but not NHEJ, is required for protection against O6-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs, DNA Repair, 8, 72-86

 

 

Mechanisms of cross-link repair

There are agents which create DNA cross-links, and are of particular importance in the tumour chemotherapy. So far, knowledge is scarce about the repair of DNA cross-links. We work with cell types which are highly sensitive to agents that create cross-links. Our understanding is that this can be traced back to DNA cross-link repair. The project aims to find out which genes and proteins are involved in DNA cross-link repair.

 

Goldstein M., Roos W., Kaina B. (2008) Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: contribution of DNA replication, transcription inhibition and Chk/p53 signalling, Toxicology and Applied Pharmacology, 229, 20-32

 

Brozovic A., Fritz G., Christmann M., Zisowsky J., Jaehde U., Osmak M., Kaina B. (2004) Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance, International Journal of Cancer, 112, 974-985

 

 

MGMT and tumour therapy

DNA repair is important not only to the cells’ protection system against UV light, X-radiation and environmental carcinogens but it also plays a role as a “resistance marker” in the tumour therapy. So, the repair protein MGMT is an eminently important resistance marker for cytostatics which have an effect on methylating drugs such as procarbazine, dacarbazine and temozolomide; and on chloroethylating drugs, such as carmustine, nimustine, lomustine and fotemustine.

Many tumours express low levels of MGMT. These tumours are probably very sensitive to the abovementioned cytostatics. We are carrying out experiments on tumour tissue with regard to MGMT activity. Furthermore, we are pursuing the strategy of blocking the MGMT protein through purposefully selected inhibitors, in order to sensitise the tumour for the therapy with alkylating agents. 

 

Strik H., Buhk J., Wrede A., Hoffmann A., Bock C., Christmann M., Kaina B. (2008) Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas, Molecular Medicine Reports, 1, 863-867

 

Wiewrodt D., Nagel G., Dreimüller N., Hundsberger T., Perneczky A., Kaina B. (2008) MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome, International Journal of Cancer, 122, 1391-1399

 

Kaina B., Christmann M., Naumann S., Roos W. (2007) MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Repair, 6, 1079-1099

 

Koch D., Hundsberger T., Boor S., Kaina B. (2007) Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma, Journal of  Neuro-Oncology, 82, 85-89

 

Kaina B., Muhlhausen U., Piee-Staffa A., Christmann M., Garcia Boy R., Rosch F., Schirrmacher R. (2004) Inhibition of O6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors: comparison with nonconjugated inhibitors and effect on fotemustine and temozolomide-induced cell death, Journal of Pharmacology and Experimental Therapeutics, 311, 585-593

 

Preuss I., Eberhagen I., Haas S., Eichhorn U., Kaufman M., Beck T., Eibl R., Dall P., Bauknecht T., Dippold W., Hengstler J., Kaina B. (1996) Activity of the DNA repair protein O6-methylguanine-DNA methyltransferase in human tumor and normal tissue, Cancer Detection and Prevention, 20, 130-136

 

 

Mechanisms of induction of apoptosis based on specific DNA damage: O6 methylguanine

Methylating cytostatics induce O6 methylguanine in DNA. DNA damage is not only mutagenic and responsible for the formation of tumours but also toxic through induction of programmed cell death (apoptosis). We have studied the mechanism of how specific DNA damage leads to apoptosis in lymphocytes, glioma and melanoma cells. The induction of apoptosis requires cell division and a functioning mismatch repair system (MMR). This complex chain of events, which leads to the death of tumour cells, operates efficiently when the tumour suppressor protein p53 is present. This implies that MGMT (which repairs O6 methylguanine), mismatch repair and p53 are resistance factors. P53 doesn’t play a strengthening role for the chloroethylating cytostatics; it inhibits apoptosis through simulation of DNA repair.


Roos W., Batista L., Naumann S., Wick W., Weller M., Menck C., Kaina B. (2007) Apoptosis in malignant glioma cells triggered by the temozolomide- induced DNA lesion O6- methylguanine, Oncogene, 26, 186-197


Kaina B., Christmann M., Naumann S., Roos W. (2007) MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Repair, 6, 1079-1099


Batista L., Roos W., Christmann M., Menck C., Kaina B. (2007) Differential sensitivity of malignant glioma cells to methylating and chloroethylating anticancer drugs: p53 determines the switch by regulating xpc, ddb2 and DNA double-strand breaks, Cancer Research, 67, 11886-11895


The project is supported by the DFG and the Mildred Scheel Foundation.