Grant: Operating Grant

The germ line cells of sexually-reproducing animals are destined to give rise to the eggs and sperm necessary for the propagation of the species. Consequently, germline DNA must be protected from acquiring mutations that will be transmitted to the next generation and can result in susceptibility to diseases like breast cancer. The DNA of all eukaryotic cells is organized into chromatin through association with a complex of histone proteins and other DNA-associated proteins. The modification of histones is known to result in changes that make the chromatin more or less accessible to proteins required for transcription of genes during development. Here, we address the role of histone modifications in facilitating the repair of unexpected DNA damage in the germ cell lineage of the nematode C.elegans. We have identified a protein, HTP-3, that is localized to the germ cells throughout development and is required to both establish a germline-specific chromatin architecture and to accurately repair DNA damage. In this proposal, we will first investigate how germline chromatin is established and the role of HTP-3 in this process. We will then examine how germline chromatin is modified in response to the presence of DNA breaks, and the role of these DNA-damage responsive chromatin changes on germ line and DNA repair processes. These experiments will reveal how the germline genome is configured and how this architecture can ensure that unexpected mutations are accurately repaired to restore an intact genome for the next generation.