DNA repair pathway decisions in normal and malignant B cells

Genetic alterations of the DNA are a main cause of cancer. These alterations not only include individual DNA base changes, but also chromosomal re-arrangements of long DNA molecules, all of which can substantially affect gene expression. Eventually, an altered expression of genes that regulate cell growth and proliferation can lead to the development of cancer. The continuous accumulation of genetic alterations is not only responsible for cancerogenesis, but also for an unfavourable course of the disease as well as for resistance to therapy, since it allows the selection of the fittest clones from a heterogeneous pool of genetically different cancer cells. An important cause of genetic alterations is dysregulated DNA repair. While DNA damage occurs constantly in every cell, DNA repair mends this damage and thereby prevents the acquisition of a genetic alteration. All cells can choose from a panel of diverse repair pathways to mend damaged or broken DNA molecules. However, while some repair pathways seem functionally redundant, they differ in their precision and error rate. The aim of this project is to identify factors responsible for DNA repair pathway decisions and for high error rates during DNA repair in some cancer cells. Methodologically, the project utilizes genetic screens as well as gene expression profiling in combination with novel repair-reporter constructs in cell lines and primary normal and leukemic cells. Normal and leukemic B cells are used for this project as a model system, because B cell leukemias have a high incidence and are easily accessible for functional assays in high quantities. Identified factors will subsequently be tested in cell lines upon their selective overexpression, silencing or modification. The knowledge gained by this project on the regulation of DNA repair will help us to better understand the (in)stability of the genome of cancer cells and to find better treatment options for cancer.