DNA repair and the DNA damage response

The human genome encodes a set of instructions that are essential for the development of a complex organism as well as the specialized function of trillions of cells within any one individual. The chemical material (i.e., DNA) that carries this information is, however, regularly damaged. Cells must therefore actively protect their genomes. To support this task, cells have the DNA damage response, a sophisticated set of mechanisms that sense, signal, and repair chemically diverse forms of DNA damage or, when damage cannot be repaired, induce programs of cell death to eliminate aberrant genomes. From decades of past work, we know a lot about the DNA damage response. We know many—if not most—of the proteins involved. We know how cells use such proteins to sense various forms of damage, and we know how damage is communicated to the cell and repaired. However, we know far less about how individual response activities are organized to respond with flexibility across conditions (e.g., cell types, chromatin states). Our research seeks to map the ‘network’ of factors that maintain genome integrity in human cells and understand how DDR mechanisms are deployed in specific contexts.

Genome editing

Genome editing technologies allow DNA sequence changes to be made to the genomes of living cells. These powerful tools have become key components of biomedical research and hold promise for addressing a host of unmet medical needs. A major trajectory of our current work is focused on understanding the complex set of DNA repair processes that impact genome editing in human cells. Typically, genome editing technologies work through a similar procedure: First, a programmable enzyme cuts, damages, or alters DNA at a targeted site in the genome. Then, a cell’s own mechanisms of DNA repair permanently install a sequence change or ‘edit’ at that site. Ideally, this approach would be absolutely precise, both in terms of where a change is made and exactly what sequence change occurs. However, while recent technical advances have made accurate DNA targeting commonplace, control over edit installation—specifying edit frequency and type—remains a key challenge. By systematically delineating the processes that enable genome editing tools, we discover ways to improve these important technologies.

Technology development

To enable our work, we build and use innovative genomics tools. These technologies leverage recent advances in CRISPR-based genetics, single-cell RNA-sequencing, and genetic interaction mapping. Among other accomplishments, we’ve discovered ways to improve genome editing tools and developed new screening approaches, including ones that enable systematic interrogation of transcriptional programs (Perturb-seq) and DNA repair (Repair-seq). Finally, through technology development efforts, we also support collaborative studies in diverse areas of biology, including virology, immunology, and development.