Department of Pharmacology
Wood Building, W343A
2109 Adelbert Road
Cleveland, OH 44106
Genome stability, in a simple way, means that the genetic information buried in nuclear DNA has to be kept stable. Changes or damages to DNA, if not fixed, often lead to the loss of genome stability. A long-term effect of the loss of genome stability is the occurrence of degenerative diseases, including premature aging, cancer, immune-deficiency, neuro-degeneration, etc. My lab is interested in understanding a fundamental biological question: how is the genome stability maintained in human cells? A primary focus of the lab is to dissect the molecular signaling networks that maintain the genome stability in human cells.
Virtually every biological process of the cell is carried out by a signaling network that is mainly composed of proteins and other molecules including RNAs. Genome stability maintenance is no exception. Knowing members of this signaling network is critical for our understanding of how the genome stability is maintained in human cells. We use biochemical, genetic, pharmacological and structural tools to identify proteins and other players involved in this process and characterize their molecular functions in cells. Below is information on our current research.
Mechanisms underlying the DNA damage response (DDR)
In response to DNA damage, cells mount an evolutionally conserved signaling pathway, called DNA damage response (DDR), to sense the presence and initiate the repair of DNA damage. This signaling pathway is critical for the maintenance of genome stability and functions as a barrier against tumorigenesis. We are interested in identifying and characterizing the function of new players (including novel genes or RNAs or genes with previously unidentified function) in DDR.
Networks controlling DNA double-strand break (DSB) repair
DNA double-strand break (DSB) is the most lethal damage to DNA. DSBs can be generated by DNA damaging agents (e.g., ionizing radiation or chemotherapeutic drugs) or can arise from physiological events (e.g., immune development or gamete production). The presence of DSBs triggers the DDR, which in turn initiates a cascade of events to facilitate the repair of DSBs by the error-free homologous recombination or the error-prone non-homologous end-joining pathway. We recently identified a new player, UbcH7, in DSB repair regulation. We are interested in understanding the detailed mechanisms governing the DSB repair choice and their impact on genome stability.
Pathways regulating aging
Another interesting research topic in the lab is to study how genes involved in DDR control the aging process. For instance, manipulating UbcH7 seems to affect cellular aging. Therefore, we are interested in dissecting the molecular mechanisms linking the DDR to aging.
The genome stability maintenance network functions as a double-edged sword. At one hand, it protects the cell's DNA from damage. On the other hand, it has remained a central target in cancer therapy. The idea underpinning this strategy is that inhibiting the genome stability maintenance network makes cancer cells extremely sensitive to agents that damage their DNA, inducing the cell-killing effect. Our laboratory is also interested in translating the knowledge that we have gained above from bench to bed. The long-term goal is to cure or control cancers to increase the quality of life in cancer patients.
Therapeutic Advances and Research Breakthroughs
Studies done in the Zhang lab have the potential to be translated into treatment for human diseases, including cancers. For instance, our recent discovery opened the door for a new way to treat cancers without the concurrent use of chemotherapeutic drugs. Therefore, this novel concept should significantly reduce the toxic side effect of chemotherapy. We wish to design a better therapy for cancer patients with more effect and less toxicity.