Characterization of the growth-regulating and anti-apoptotic activity of the recombination factor Rad51 in tumorigenesis

Genome damage is the starting point of causal chains that lead to mutations, cellular metabolic disorders, or cancer. New findings demonstrate a close connection between signaling pathways that originate from DNA damage and lead to damage repair, cell cycle regulation, differentiation, the induction of mixed instability, and apoptosis/necrosis. The molecular consequences of pathological alterations in key DNA repair factors and their contribution to the development of malignant cancers are not yet understood. This study aims to investigate whether the development of therapy-resistant new tumor cell populations is a consequence of dysregulation of the DNA repair and recombination factor Rad51 and a resulting selective advantage for these cells.
Key new aspects of the studies include detailed analyses of the mechanisms of Rad51-induced modulation of cell proliferation and cell death, taking into account functional interactions with the tumor suppressor p53; the identification of differentially expressed genes dependent on Rad51 expression; the characterization of the mode of action of newly identified chemical compounds that preferentially kill cells with high Rad51 content; and the establishment of a transgenic mouse model that can be used to simulate the overexpression of Rad51 observed in human tumors and investigate its effects on tumorigenesis. The comparison of these parameters will contribute significantly to elucidating the interplay between processes of proliferation regulation, DNA repair, and the maintenance of cellular genetic integrity and thus provides the basis for the development of a Rad51-based tumor therapy.