The inappropriate repair of double-strand breaks can lead to chromosomal translocations in somatic and germline cells. These events are causative for many diseases, including cancer. The goal of this project is to examine the influence of chromatin architecture in DSB repair. How broken ends of different chromosomes meet in the cell nucleus to form a translocation event is not well understood. Our current understanding of these activities is limited to the context of open vs. closed chromatin, excluding the role of higher order structures. However, it has been become increasingly evident that the spatial organization of chromatin must influence double-strand break formation and repair. I will study the relationship between chromatin architecture and double-strand break formation and repair in the context of meiosis where DSBs occur in a controlled and predictable manner. The DNA transactions that occur in meiosis will provide a molecular readout of the influence of chromatin architecture on DSB formation and repair that is not available in studies of organized mitotic chromosomes. I will define chromatin loop architecture in meiosis by mapping meiotic ohesion to both mouse and yeast genomes. These maps will enable me to utilize a technique termed chromatin conformation capture technique (3C) that will provide high-resolution details for how chromatin architecture influences DSB formation and repair in vivo. )
Chromosomal translocations are induced by double-strand breaks (DSBs) that occur continuously in the genome through the action of DNA-damaging agents and during genome replication. A role for higher-order chromatin structure in double-strand break repair is obvious, yet the study of this role has been neglected. This proposal aims to understand the molecular mechanism that underlies tumor promoting translocations and the specific strategies used by normal cells to protect the genome against such deleterious DNA rearrangements. ) )
| Sasaki, Mariko; Tischfield, Sam E; van Overbeek, Megan et al. (2013) Meiotic recombination initiation in and around retrotransposable elements in Saccharomyces cerevisiae. PLoS Genet 9:e1003732 |
