Simple alkylating agents are not only found in the environment, food and tobacco smoke but are also formed during the natural metabolic process in the body. These molecules cause modifications to the bases in DNA, and when these modified bases are not repaired can give rise to mutation, cancer formation or cancer progression. Another interesting aspect of these methylation or alkylation modifications is that they can cause the cell to undergo the controlled process of cell suicide (apoptosis). This may be a defense mechanism evolved by multi-cellular organisms for eliminating cells containing compromised DNA that may be detrimental to the organisms survival. In other words, when a cell fails to repair the alkylation damage in its DNA it may opt to completely remove itself from the cell population, thereby giving the organism as a whole a better chance for survival. This becomes very important when considering stem cells as these cells contain the ability to give rise to many different cell types in the organism and can therefore would transfer mutations to their progeny. This interplay between the repair of DNA damage and what happens when cells are unable to repair the damage are of interest to us working in the field of DNA damaged signaled apoptosis.
Apart from the naturally accruing alkylation load a cell have to deal with every day, special circumstances exist where cells are exposed to huge levels of this kind of damage. Specifically during cancer therapy, as simple alkylating agents (temozolomide and carmustine) are used for the treatment of glioblastoma, melanoma and certain types of lymphoma. We are interested in the molecular mechanisms required by cancer cells to undergo apoptosis following alkylation damage. Ideally by using the information obtained in the lab we would be able to increase sensitivity in cancer cells while decreasing sensitivity in normal tissue, thereby improving the overall treatment efficiency for these tumor types.
The day to day work in the lab consists of defining not only classical cellular mechanisms, like DNA repair, DNA synthesis, cell cycle control, cell signaling and apoptosis, but also to identify novel players and mechanisms following the cells exposure to alkylating agents.
Quiros S., Roos W., Kaina B. (2010) Processing of O6-methylguanine into double strand breaks requires two rounds of DNA replication whereas apoptosis is also induced in subsequent cell cycles. Cell Cycle, 9, 168-178
Roos W., Tsaalbi-Shtylik A., Tsaryk R., Güvercin F., de Wind N., Kaina B. (2009) The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs. Molecular Pharmacology, 76, 927-934
Batista L., Roos W., Kaina B., Menck C. (2009) p53 mutant human glioma cells are sensitive to UV-C-induced apoptosis due to impaired cyclobutane pyrimidine dimer removal. Molecular Cancer Research, 7, 237-246
Naumann S., Roos W., Jöst E., Belohlavek C., Lennerz V., Schmidt C., Christmann M., Kaina B. (2009) Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53. British Journal of Cancer, 100, 322-33
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 O(6)-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs. DNA Repair (Amst), 8, 72-86
Goldstein M., WP. Roos and B. Kaina (2008) Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: Contribution of DNA replication, transcription inhibition and Chk/p53 signaling. Toxicology and applied Pharmacology, 229, 20-32
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
Roos W., Christmann M., Fraser S., Kaina B. (2007) Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair. Cell death and differentiation, 14, 1422-1432
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., 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 O-6-methylguanine. Oncogene, 26, 186-197
Roos W., Kaina B. (2006) DNA damage-induced cell death by apoptosis. Trends in molecular medicine, 12, 440-450
Hermisson M., Klumpp A., Wick W., Wischhusen J., Nagel G., Roos W., Kaina B., Weller M. (2006) O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. Journal of neurochemistry, 96, 766-776
Roos W., Baumgartner M., Kaina B. (2004) Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. Oncogene, 23, 359-367
Dunkern T., Roos W., Kaina B. (2003) Apoptosis induced by MNNG in human TK6 lymphoblastoid cells is p53 and Fas/CD95/Apo-1 related. Mutation research/ Reviews in mutation research, 544, 167-172
Funded by the Mildred Scheel Foundation.