Biochemistry and Regulation of Mammalian DNA Repair

DNA base excision repair (BER) is the principal DNA repair system in cancer cells, which counteracts the killing effect of major cancer treatments e.g., chemotherapy and ionizing radiation. Changes in BER capacity most probably are responsible for the efficiency of cancer treatment, as many cancers have an altered amount of BER proteins. Although BER proteins have been studied in detail, the mechanisms involved in BER coordination, their regulation and consequences of their malfunction are unclear. This gap in knowledge is impeding the discovery of new cancer therapy targets and the development of novel cancer treatment strategies. The objective of the Biochemistry Group is to identify new mechanisms and proteins that are responsible for the coordination and regulation of the BER pathway in human cells and to understand their role in processing endogenous and radiation induced DNA lesions, with a final goal to improve the efficiency of cancer therapy.

DNA base excision repair (BER) is the principal DNA repair system in cancer cells, which counteracts the killing effect of major cancer treatments e.g., chemotherapy (alkylating agents) and ionizing radiation (about 80 % of DNA damage induced by ionizing radiation are SSBs and base lesions which, as a result of BER, can be converted to DSBs during DNA replication). Changes in BER capacity most probably are responsible for the efficiency of cancer treatment, as many cancers have an altered expression of BER proteins. Although BER enzymes have been studied in detail, the mechanisms involved in BER coordination, their regulation and consequences of their malfunction are unclear. This gap in knowledge is impeding the discovery of new cancer therapy targets and the development of novel treatment strategies. The objective of the Biochemistry Group is to identify new mechanisms and proteins that are responsible for the coordination and regulation of the BER pathway in human cells and to understand their role in processing endogenous and radiation induced DNA lesions, with a final goal to improve the efficiency of cancer therapy. Our recent studies have allowed us to formulate the basic principles behind the regulation of steady state levels of BER proteins and coordination of the BER process with cell cycle progression. Consequently, the major goal of future studies would be to build a comprehensive model for regulation and coordination of the BER response to ionizing radiation in order to identify new targets for improvement of cancer radiotherapy. To achieve our goal we will:
1. Investigate the mechanisms regulating the transcription of BER genes and their regulation under DNA damage stress.
2. Study the role of ATM in regulation of BER gene expression.
3. Address the effect of BER deficiency on cellular gene expression and its role in tumorigenesis.
4. Search for new genes involved in DNA damage response which are synthetically lethal with BER genes.