Tim J. Yen, PhD
Office Phone: 215-728-2590
Lab Phone: 215-728-4311
Growth of multicellular organisms is critically dependent on the ability of individual cells to duplicate and separate their genomes during cell division. Defects in DNA replication and chromosome segregation can lead to significant human health problems that include cancer, birth defects and infertility. The mechanisms that are responsible for replicating the genome and to segregate the resultant chromosomes during mitosis can be viewed as mechanical events because the proteins involved in these functions are molecular machines. Superimposed on the mechanical processes are regulatory mechanisms called checkpoints that monitor the molecular machines to ensure that their tasks are accomplished accurately and in a timely manner. Thus, checkpoints play an essential role in maintaining genome stability by ensuring that errors in DNA replication and chromosome segregation are corrected before cells are allowed to divide.
Our laboratory is focused on understanding the mechanical and regulatory mechanisms that ensure that chromosomes are properly attached and segregated by the spindle during mitosis. We have focused our attention on characterizing the molecular composition and function of the kinetochore, as this is the structure on the chromosome that establishes and monitors connections with microtubules. We have identified molecular motors and checkpoint proteins that reside at kinetochores and are interested in understanding how these proteins interact with each other to carry out complex kinetochore functions. Our research is particularly relevant to cancer research as drugs that inhibit mitosis are a major modality for anti-cancer therapy. Current drugs however, lack specificity as they target microtubules that provide functions that not only are critical for mitosis but also for other essential cellular processes such as vesicle transport, cell shape and locomotion. Our studies of how chromosomes segregate have revealed novel proteins that provide functions that are critical only during mitosis. As such, these proteins should be ideal candidates for the development of highly specific anti-mitotic drugs.Description of research projects
Fox Chase Programs
- Beeharry N, Yen TJ. p53-dependent apoptosis in response to spindle damage linked to loss of Bub1. Cancer Biol Ther 2009; 8 (7). PubMed
- Zhang XD, Goeres J, Zhang H et al. SUMO-2/3 modification and binding regulate the association of CENP-E with kinetochores and progression through mitosis. Mol Cell 2008; 29 (6):729-41. PubMed
- Liu ST, Yen TJ. The kinetochore as target for cancer drug development. In: PD Wulf; WC Earnshaw, editors, translator and editor The Kinetochore from Molecular Discoveries to Cancer Therapy: Springer; 2008.
- Huang H, Hittle J, Zappacosta F et al. Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit. J Cell Biol 2008; 183 (4):667-80. PubMed
- Huang H, Fletcher L, Beeharry N et al. Abnormal cytokinesis after X-irradiation in tumor cells that override the G2 DNA damage checkpoint. Cancer Res 2008; 68 (10):3724-32. PubMed