A Life on Holliday

September 20th 2018, 2pm / Centre de Recherche - Paris - Amphithéâtre Constant-Burg - 12 rue Lhomond, Paris 5e Steve West

Our genetic material (DNA) is continually subjected to damage, either from endogenous sources such as reactive oxygen species that arise as by-products of oxidative metabolism, from the breakdown of replication forks during cell growth, or by agents in the environment such as ionizing radiation or carcinogenic chemicals. To cope with such damage, cells employ a variety of repair processes that are specialized to recognize different types of lesions in DNA. These repair systems are essential for the maintenance of genome integrity and for cancer avoidance.  

The focus of our research is to determine the mechanisms for repair and to define the cellular defects that lead to cancers and neurodegeneration, two common consequences of defective damage processing. In particular our efforts focus on the mechanisms of homologous recombination, which are important for the repair of double-strand breaks in DNA. Defects in this process lead to cancer predisposition, in particular breast cancers caused by mutation of the BRCA2 gene, acute leukemias associated with Fanconi anemia, and a wide range of cancers found in individuals with the chromosome instability disorder known as Bloom’s syndrome. Over the years, many of the proteins required for recombinational repair have been purified in our laboratory, and we use biochemical, structural, and molecular and cell biological approaches to understand how they bring about the repair of DNA breaks. Of particular interest are the roles of the BRCA2 tumour suppressor and the RAD51 recombinase in mediating the initiation of recombinational repair. Studies of the enzymes (MUS81-EME1 and GEN1) that mediate the resolution of DNA recombination intermediates (e.g. Holliday junctions) reveals an unexpectedly tightly controlled system that is essential not just for the completion of recombinational repair, but also for the proper segregation of DNA at mitosis. The lecture will describe our current understanding of recombinational repair and why defects in this process leads to human disease.