RNDr. Mario Špírek, Ph.D.

Project: HR51RK - Rapid kinetics of human recombinational machinery

Person in Charge: Mgr. Lumír Krejčí, Ph.D.

Host institution: Faculty of Medicine, Masaryk University

Country of Origin: Slovakia

Country of scientific activity: Hungary, USA

Project duration: 24 months

Scientific panel: Life sciences

Abstract:

The repair of damaged DNA is vital for the maintenance of genome integrity. One of the mechanisms to restore continuity of DNA is homologous recombination with Brca2 protein being among the key players in this mechanism. Mutations in this gene represent the cause of a significant portion of familial breast cancers and confer an increased risk of ovarian, pancreatic, and prostate cancer. Moreover, the inactivation of BRCA2 gene function can also result in the cancer prone-syndrome Fanconi anemia underscoring the relevance of our choice for its detailed study, yet the molecular function of Brca2 protein remains poorly understood. BRCA2 likely exerts its tumor suppressor function by enhancing the efficiency of the homology-directed repair of damaged DNA. In this project, the aim is to characterize the level of quality control of Rad51 mediated reactions. This includes the recombination mediator function of BRCA2 and details of the clearing Rad51 polymers by Recq5 helicase and thus to define the molecular basis for these functions. To achieve research goals, rapid kinetics study of different domains of BRCA2 will be carried out in relation to stabilization or destabilization of Rad51 self-assemblation into an extended polymer on single-stranded DNA. Moreover, the molecular mechanisms of the RecQ5 suppression of the recombination will be tested using rapid kinetic studies with respect to protecting activity of Brca2 on Rad51 filaments. By deciphering the functional significance of these interactions, we will be able to rationalize how BRCA2 functions in the genome instability and breast cancer. It is possible that the components of BRCA2 pathway might also be direct targets of tumorigenesis and dissecting BRCA2 pathway should reveal such targets.