We study how cellular machinery detects, signals, and repairs DNA lesions, a collective network known as DNA damage response (DDR). Many human diseases are associated with DDR defects, including developmental abnormalities, accelerated aging, and common cancers. Therefore, a profound understanding of DDR will not only elucidate how life maintains genetic stability but also provide valuable insights for disease therapeutics.

Our laboratory aims to decipher the extensively interconnected DDR pathways inside living cells. In particular, we are interested in the physical and chemical principles governing DNA repair processes. Conventional assays using chemical mutagens and physical radiation struggle to recapitulate cellular responses to distinct types of DNA lesions on targeted genome sequences, structures, and functional compartments. At the University of Utah, we leverage state-of-the-art chemical biology, genomics, and microscopy techniques to explore DDR processes within its genomic and cellular context. Specifically, we will 1) build a versatile CRISPR toolkit for on-demand genome perturbation; 2) establish CRISPR-based strategies for nucleic acids imaging; 3) profile chromosome dynamics at the systems level, emphasizing the proteomic and structural changes during DNA repair.

We recently developed a controllable CRISPR-Cas9 technology, termed very fast CRISPR (vfCRISPR) (Liu et al., Science 2020). With photocaged nucleotides integrated into its guide RNA, the vfCRISPR system can induce DNA double-strand breaks (DSB) after light stimulation and with second-scale temporal resolution. This enabling technique, akin to the ‘Channelrhodopsin’ in optogenetics, allows ultrafast genome perturbation and is compatible with multi-omics and imaging methods to capture the molecular changes in DSB repair. Together, our interdisciplinary research in nucleic acids, gene editing, and cellular biophysics will significantly deepen our knowledge of genome maintenance and shed light on improving biotechnologies for precision genome editing.

vfCRISPR in action under light (gRNA, gold; DNA, red)