Fangfang Wang, a postdoctoral scholar in the Department of Pharmacology, was recently awarded an American Cancer Society Postdoctoral Fellowship.
Over three years, Wang will study 53BP1 phase separation in genome stability and cancer.
Wang is mentored by Youwei Zhang, professor in the Department of Pharmacology at the School of Medicine.
Maintaining the stability of the genome (a complete set of DNA and associated structures) is a core biological principle for all living organisms. Anything that disrupts the long-term stability of the genome, including DNA mutability, faulty DNA repair, chromosome segregation error, etc., can profoundly affect biological life.
In humans, genomic instability is a root cause of cancer progression. Hence, understanding mechanisms regulating genome stability has a huge impact on cancer biology and therapy. Unfortunately, mechanisms maintaining genome stability are complex and not well understood, impairing our understanding of biology and cancer.
Biomolecule compartmentalization is an ancient biological process, through which certain proteins are enriched in a particular cellular microenvironment to regulate cellular function. Traditionally, this compartmentalization has been viewed through the formation of organelles with membrane boundaries such as the nucleus, the mitochondrion, the Golgi apparatus, etc. In the recent decade, a novel theme in biological compartmentalization called liquid-liquid phase separation (LLPS) has been increasingly appreciated, through which proteins, nucleic acids, and other molecules form membraneless liquid droplets/condensates in cells.
Unlike membrane-containing organelles, LLPS allows rapid assembly/disassembly of functional proteinaceous organelles following environmental or internal cues, providing an innovative means to regulate biology and pathophysiology.
Hypothesis related to genome stability regulation has long been revolved around the DNA damage response and repair programs.
Wang and Zhang recently discovered a novel link between LLPS and genome stability, in which a protein called 53BP1 preserves chromosome structure and function through undergoing LLPS; further, this new LLPS activity of 53BP1 is independent of its widely known role in
DNA double strand break (DSB) repair. This finding opens a new paradigm of genome stability
regulation (i.e., chromosome structure stability and associated epigenetic memory maintenance mediated by LLPS). The overarching goal of this proposal is to establish this research paradigm and to fill the knowledge gap by determining both the molecular basis and the impact of LLPS on genome stability regulation.
The researchers will integrate CRISPR-based genome editing, chemical-induced protein proximity dimerization, and high throughput sequencing to accomplish this goal.
They expect to create a leading edge and to make breakthroughs in their understanding of genome stability regulation with a long-term goal to better understand cancer and to