CAREER: High-resolution profiling of histone modifications responsible for heterochromatin repair

University Of Southern California, Los Angeles CA

Investigators

Abstract

Abstract DNA is continually subject to damage and life depends on repairing it. The consequences of failure are especially high in heterochromatin, the which mostly consists of highly compact DNA-protein structures and repeated DNA sequences. While repair failures in normal chromatin can lead to deleterious mutations, incorrect repair within repetitive heterochromatic regions can trigger rearrangements that cause cell death or genome instability. This project will use new experimental approaches and methods in the fruit fly to understand heterochromatic repair pathways at the chromatin level. This work will yield fundamental advances in our understanding of the role of chromatin modifications on genome integrity, and the project itself creates excellent educational opportunities for junior researchers to participate in training, teaching, mentoring and outreach activities, launching their careers in science while inspiring others. Specific attention for inclusion of undergraduate and high school students from underrepresented groups will expose more women and low-income students to STEM fields. These research and educational activities will increase their career opportunities while diversifying the pipeline of future scientists and broadening perspectives to solve future societal challenges. This project will also involve organizing a "SoCal Genome Stability" symposium that will enhance the dissemination of knowledge, open new networking, research and career opportunities for junior and senior scientists at colleges and universities across Southern California. Nearly 30% of the human genome comprises pericentromeric heterochromatin, where defective repair of double-strand breaks (DSB) can lead to widespread genome rearrangements. Previous studies revealed specialized mechanisms required for 'safe' homologous recombination (HR) repair of these sequences, including a poorly understood role for histone marks. This study will shed light on the role of chromatin composition and regulation in heterochromatin repair in Drosophila. It will combine the unique strengths of the Drosophila model system, with innovative tools for site-specific DSB induction and next-generation sequencing. This combination of approaches will enable the first high-resolution profiling of chromatin dynamics responsible for heterochromatic repair, significantly advancing the understanding of genome stability mechanisms in multi-cellular eukaryotes.