Emmanuel Skordalakes, Ph.D.

Assistant Professor
Gene Expression and Regulation Program
215-495-6884, Office
215-898-2202, Lab

Introduction

The focus of my research lies with protein nucleic acid assemblies that participate in the replication and maintenance of eukaryotic chromosome ends, called telomeres. Telomeres protect chromosome ends from gradual length erosion, prevent end-to-end fusions and recombination, and promote proper chromosome partitioning during meiosis. Telomere length deregulation and telomerase activation are early and perhaps necessary steps in cancer cell evolution. Furthermore, telomerase and telomere dysfunction are thought to contribute to replicative senescence and programmed cell aging. Despite these fundamental roles in maintaining genome integrity and cell fate, surprisingly little is known about the molecular basis of telomere synthesis by telomerase. We are interested in elucidating the mechanism of telomere replication by telomerase and understand how telomere and telomerase binding proteins regulate telomerase activity and protect chromosome ends. The lab primarily uses structural methods coupled with biophysical and biochemical techniques to study the above systems.

Research Summary

Telomerase Function

Telomere replication is mediated by telomerase, an RNA dependent DNA polymerase structurally similar to retroviral reverse transcriptases and viral RNA polymerases. 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 mechanisms of telomere replication and length homeostasis. It will further enrich our understanding of the mechanism of DNA replication by polymerases in general. It will 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.

Telomerase Regulation

In recent years, a number of factors essential for telomerase regulation and telomere maintenance have been identified. 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.

Selected Publications

Mitchell M, Gillis A, Futahashi M, Fujiwara H, Skordalakes E. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA.Nature Structural & Molecular Biology. 2010 Apr;17(4):513-8. [Epub 2010 Mar 28] 20357774

Gillis AJ. Schuller AP. Skordalakes E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 2008 Oct 2.455(7213):633-7. [E-pub 2008 Aug 31] 18758444

Rouda S. Skordalakes E. Structure of the RNA-Binding Domain of Telomerase: Implications for RNA Recognition and Binding. Structure. 15(11):1403-1412, 2007 Nov 13. 17997966

Skordalakes, E. Berger, JM. Structural insights into RNA-dependent ring closure and motor domain activation by the Rho transcription termination factor. Cell. 127(3):553-64, 2006 Nov 3. 17081977

Skordalakes E. Brogan AP. Park SB. Kohn H. and Berger JM. Structural mechanism of  inhibition of the Rho transcription termination factor by the antibiotic icyclomycin. Structure. 13(1):99-109, 2005 Jan. 15642265

Daganzo SM. Erzberger JP. Lam WM. Skordalakes E. Zhang R. Franco AA. Brill SJ. Adams PD. Berger JM. Kaufman PD. Structure and function of the conserved core of histone deposition protein Asf1. Current Biology. 13(24):2148-58, 2003 Dec 16. 14680630

Skordalakes E. Berger JM. Structure of the Rho transcription terminator: mechanism of mRNA recognition and helicase loading. Cell. 114(1):135-46, 2003 Jul 11. 12859904

Hansen CL. Skordalakes E. Berger JM. Quake SR. A robust and scalable microfluidic metering method that allows protein crystal growth by free interface diffusion. Proceedings of the National Academy of Sciences of the USA. 99(26):16531-6, 2002 Dec 24. 12486223