Greehey CCRI Seminar Series, Spring ’24: Ben E. Black, Ph.D. (University of Pennsylvania)

Description of Research:
The longest standing goal of my lab has been to understand how particular proteins direct accurate chromosome segregation at mitosis and meiosis. In humans, the chromosomal element—the centromere—that directs this process is not defined by a particular DNA sequence. Rather, the location of the centromere is dictated by an epigenetic mark generated by one or more resident proteins. These centromeric proteins interact directly with the DNA to create a specialized chromatin compartment that is distinct from any other part of the chromosome. By taking biophysical, biochemical, genetic, epigenomic, and cell biological approaches, our work is to define the composition and physical characteristics of the protein and protein/DNA complexes that epigenetically mark the location of the centromere on the chromosome. This work involves building centromeric chromatin from its component parts for analysis of its physical characteristics, developing biochemical assays to reconstitute steps in the process of establishing and maintaining the epigenetic mark, exploiting emerging genomic and epigenomic technologies to investigate the structure of centromeric chromatin, and using cell and organismal approaches to study the behavior of proteins involved in centromere inheritance and other essential aspects related to chromosome segregation at cell division. We are using the understanding gained from this work to advance technologies for building synthetic chromosomes for applications in research and medicine. An exciting new area of interest for my group to emerge in the last several years has been with the enzyme PARP-1: a key component for signaling DNA damage and an important clinical target for small molecule inhibition. Our work with PARP-1 has defined the allosteric network that potently activates the enzyme upon binding to a DNA break. Most recently, we have discovered that clinical PARP inhibitor (PARPi) compounds fall into three distinct types, depending on their allosteric modulation of DNA binding affinity. Our collaborative team is using this understanding to develop ‘designer’ PARPi compounds where the allosteric effects they confer are tuned for either strong DNA retention (i.e. potent for cancer cell killing) or strong DNA release (i.e. for inhibiting PARP-1 activity in neuroinflammatory and cardiovascular disease where preserving cell viability is the goal).