Lab In The News
The Skordalakes Laboratory
The laboratory of Emmanuel Skordalakes studies the nucleoprotein assemblies that participate in the replication and maintenance of chromosome ends, known as telomeres. Telomeres protect the chromosome ends from gradually eroding during DNA replication and they prevent chromosomes from fusing and recombining thus providing the genomic stability required for cell viability. Telomeres do, however, gradually become shorter, a process that is partly responsible for the aging process. Furthermore, telomere length dysregulation is a hallmark—and perhaps necessary part—of the cancer cell evolution. The Skordalakes laboratory uses mostly structural, biochemical and cell-based assays to elucidate the function of telomerase, the enzyme that is mainly responsible for telomere replication, and complexes that regulate and maintain the length and integrity of telomeres. The laboratory is also interested in identifying small molecule modulators of telomerase activity as potential therapeutics for cancer and age-related diseases.
Joseph Kelich, Ph.D.
Motivated candidates are encouraged to inquire about the positions below. Please contact skorda@Wistar.org.
Telomere replication is mediated by telomerase, a ribonucleoprotein reverse transcriptase structurally similar to retroviral reverse transcriptases. Biochemical studies on telomerase for more than two decades have provided a wealth of information regarding telomerase function and substrate specificity. Despite this information, the biophysical mechanisms underlying telomerase architecture and function are poorly understood. Our goal is to further elucidate the molecular basis of telomere replication by telomerase using structural and biochemical approaches. The information generated here should provide novel insights into the basic mechanism of telomere replication and length homeostasis. It will further enrich our understanding of the mechanism of DNA replication by polymerases and reverse transcriptases in general. It will also provide a framework to design small molecule inhibitors of telomerase that may be of therapeutic value for cancer and other diseases associated with cellular aging.
In recent years, a number of factors essential for telomerase regulation and telomere maintenance have been identified, including the CTS and shelterin complexes. The method by which telomerase and associated regulatory factors physically interact and function with each other to maintain appropriate telomere length is poorly understood. Structural and biochemical characterization of these factors, both in isolation and in complex with one another will facilitate our understanding of how the proper function of these factors impacts telomerase function and cell proliferation.
Shastrula, P.K., Rice, C.T., Wang, Z., Lieberman, P.M., Skordalakes, E. "Structural and functional analysis of an OB-fold in human Ctc1 implicated in telomere maintenance and bone marrow syndromes." Nucleic Acids Res. 2018 Jan 25;46(2):972-984. doi: 10.1093/nar/gkx1213.
Rice, C., Shastrula, P.K., Kossenkov, A.V., Hills, R., Baird, D.M., Showe, L.C., Doukov, T., Janicki, S., Skordalakes, E. "Structural and functional analysis of the human POT1-TPP1 telomeric complex." Nat Commun. 2017 Apr 10;8:14928. doi: 10.1038/ncomms14928.
Hoffman, H., Rice, C., Skordalakes, E. "Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes." J Biol Chem. 2017 Mar 17;292(11):4593-4601. doi: 10.1074/jbc.M116.771204. Epub 2017 Feb 1.
Bryan, C., Rice, C., Hoffman, H., Harkisheimer, M., Sweeney, M., Skordalakes, E. "Structural Basis of Telomerase Inhibition by the Highly Specific BIBR1532." Structure. 2015 Oct 6;23(10):1934-1942. doi: 10.1016/j.str.2015.08.006. Epub 2015 Sep 10.
Hoffman, H., Skordalakes, E. "Crystallographic Studies of Telomerase." Methods Enzymol. 2016;573:403-19. doi: 10.1016/bs.mie.2016.04.006. Epub 2016 May 10.
Louise C. Showe, Ph.D.
Professor, Molecular & Cellular Oncogenesis Program, The Wistar Institute Cancer Center
Associate Director, Center for Systems and Computational Biology
Scientific Director, Genomics and Bioinformatics Facilities
David W. Speicher, Ph.D.
Professor and Program Co-Leader, Molecular & Cellular Oncogenesis Program, The Wistar Institute Cancer Center
Director, Center for Systems & Computational Biology
Member, The Wistar Institute Melanoma Research Center
Scientific Director, Proteomics & Metabolomics Facility