Dr. Youwei Zhang joins Pharmacology Faculty
Dr. Zhang will join the faculty at Case in the spring of 2009 as Assistant Professor of Pharmacology. Dr. Zhang received his Ph.D. from Tokyo Medical & Dental University in 2002, where he worked in Dr. Ikuo Morita’s laboratory investigating the role of a gap junction gene, connexin 43, in suppressing tumor growth through regulating the G1/S phase cell cycle transition. In 2003, Dr. Zhang joined Dr. Robert T. Abraha's laboratory at the Burnham Institute in La Jolla, to study the DNA damage response and replication checkpoint. He then moved to Dr. Tony Hunter’s laboratory at the Salk Institute in 2005 to continue working on the ATR-Chk1-regulated replication checkpoint. Dr. Zhang has published numerous primary research papers in journals such as Molecular Cell, Cancer Research, Oncogene, Cell Cycle, The Journal of Biological Chemistry, and The Journal of Cellular Physiology. His latest research on replication checkpoint has lead to novel models of the cellular mechanisms of replication checkpoint termination and anticancer therapy resistance, demonstrating that degradation of Chk1 provides a negative feedback loop to terminate the activated replication checkpoint, and that Chk1 degradation defects is centrally involved in anticancer therapy resistance.
Research Interests
Eukaryotic cells have evolved an elaborate network of genome surveillance and repair proteins to insure that DNA replication occurs in an accurate and timely fashion. This surveillance pathway is termed the S-phase replication checkpoint. The replication checkpoint monitors the progress of replication forks, and when the fork stalls, transmits signals that delay S-phase progression, and maintain the stability of stalled forks so that DNA replication can resume after the initial error is corrected. Two key components of the replication checkpoint are the apical protein kinase, ATR, and its downstream target kinase, Chk1. Replicative stress induces activation of ATR, which then induces activation of Chk1 through phosphorylating it at Ser317 and Ser345. Activated Chk1 will activate a cascade of downstream effectors, which will eventually induce cell cycle arrest and damage repair to maintain cell survival, or cell death if the damage is too severe to be repaired. Dr. Zhang’s latest research illustrated a spatiotemporal regulation of Chk1, in which replication stress induces phosphorylation and subsequent release of Chk1 from chromatin-enriched compartment to soluble nuclear and cytoplasmic compartments, where it carries out the cell cycle checkpoint functions, as well as being degraded. Dr. Zhang is interested in pursuing the precise molecular mechanisms underlying Chk1 phosphorylation and translocation.
Through his research, Dr. Zhang also provided biological significance of the ATR-Chk1 pathway, demonstrating that regulating the protein level of Chk1 is centrally involved in the anticancer therapy resistance. Dr. Zhang provided evidence that Chk1 degradation defects contribute to cancer cell resistance to both chemo- and radio-therapy. Currently, one of Dr. Zhang’s aims is to understand the mechanisms of Chk1 degradation defects in therapy resistant cancers and to build a strategy to specifically kill those resistant cancers through targeting Chk1.