We investigate the fundamental molecular mechanisms regulating repair of double-strand breaks (DSBs) in mitotic and meiotic cells. We are also interested in understanding the mechanisms directing the proper segregation of homologous chromosomes during meiosis. We use a combination of different approaches ranging from the reconstruction of in vitro systems using purified proteins to the generation of genetically modified mice.
Genome integrity is challenged by DNA damage from both endogenous (replication form staling, oxidative damage, etc) and environmental sources (ionizing radiation and pollution among others). One of the most dangerous types of DNA damage is DSBs. Therefore, repair of DSBs is of critical importance for maintenance of genome instability and avoidance of genome rearrangements and tumorigenesis. Cells have at least two mechanisms to repair DSBs, homologous recombination (HR) and non-homologous end joining (NHEJ) (Figure 1). HR is a high-fidelity mechanism and requires the presence of an identical or nearly identical sequence to template for repair of the break. Importantly, recombination is also required to ensure proper segregation of meiotic chromosomes (see below). Alternatively, NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. However, NHEJ directly joins the two ends which can introduce mutations during repair. In this case, loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms translocations.
Our laboratory integrate in vivo analysis of mouse meiosis and in vitro studies of biochemical mechanisms of recombination providing a comprehensive understanding of the role specific proteins and mechanisms involved in DSB repair and its interlink with homologous chromosome dynamics. Specifically, we are interested in:
- Understanding the mechanism of homology-directed repair of DNA double-strand breaks in the mouse and humans. For these studies we employ a combination of biochemical, biophysical, and genetic approaches.
- Investigating the role of chromatin modifications and chromatin modification complexes in DNA DSB repair and the maintenance of genome instability.
- Exploring how chromosome mechanics are coordinated with recombination and how homologous chromosome interactions are regulated.
- Understanding molecular mechanisms promoting faithful meiotic chromosome segregation and their regulation during meiotic progression.