YOU ARE EXPLORING
Suk-Hee Lee, PhD
Professor of Biochemistry & Molecular Biology
Dr. Lee received a PhD in Microbiology from the University of Texas at Austin in 1987 in the laboratory of James R. Walker where his research focused on functional analysis of DNA polymerase III (Pol III) in E. coli and explored that the tau subunit of DNA Pol III possesses DNA-dependent ATPase activity. As a postdoc, he worked in the nucleic acid laboratory of Dr. Jerard Hurwitz at the Sloan-Kettering Cancer Center, NY, where he studied simian virus 40 (SV40) DNA replication in vitro, focusing on DNA polymerases delta and epsilon and their accessory factors to understand functions of DNA replicative polymerases in human. In 1992, he joined the faculty of the Virology and Molecular Biology department at St. Jude Children’s Research Hospital, Memphis, TN where his research areas include functional analysis of DNA pol III and human replication protein A (RPA), and regulation of DNA replication following DNA damage. Since joining the Department of Biochemistry & Molecular Biology at the IU School of Medicine in 1997, his work focused on the mechanism of DNA replication and repair in humans, including functional analysis of DNA polymerases alpha and delta, RPA, XPA, XPG, DNA-PK, and Ku70/80. Dr. Lee also focused on the role of two novel human proteins with exonuclease activity, Metnase (also known as SETMAR) and EEPD1. This work is in collaboration with investigators at the University of Florida School of Medicine and the Colorado State University. Metnase is a SET-transposase fusion protein that does not function as a classic transposase, but it uses biochemical properties of the SET and the transposase domains to promote non-homologous end-joining (NHEJ) repair and restart of stalled replication fork. EEPD1 has two N-terminal helix-hairpin-helix DNA binding domains related to RuvA, and a C-terminal DNase I-like domain in the exonuclease-endonuclease-phosphatase (EEP) family. Both Metnase and EEPD1 possess the 5’ endonuclease activity that enhances Exo1 nuclease activity at fork structures. His recent work explored that EEPD1 plays an essential role in initiating homologous recombination (HR) repair of stalled replication forks.
The human genome is littered with sequences derived fromtransposable elements from the Hsmar1 transposon, but there is only one intact copy of the Hsmar1 transposase gene termed Metnase (also known as SETMAR) that exists within a chimeric SET-transposase fusion protein. Although Metnase retains most of the transposase activities, it has evolved as a double-strand break (DSB) repair protein in anthropoid primates. Metnase is localized on chromosome 3p26, a region of frequent abnormalities in various cancers and is highly expressed in most tissues and cell lines. Mutations in Metnase that cause early termination were found in many transformed cell lines, although clinical relevance of these mutations has not been established. Our long-term goal is to understand how a protein with transposase activity in humans promotes DSB repair and chromosome decatenation, and what role the SET domain may play. Given that Metnase requires both the SET and transposase domains for its function(s) in DSB repair, we hypothesize that the acquisition of new functions may have resulted from a chimeric fusion between transposase and the SET domains. Our ongoing study is to elucidate the mechanism of this human SET-transposase protein in DSB repair and chromosome decatenation.
My lab is also interested in cisplatin damage and its repair in humans. Cisplatin is a widely used anti-cancer chemotherapeutic drug that induces DNA damage by forming cisplatin-DNA adducts in cells. In vivo and in vitro studies strongly suggest that most of the cisplatin-DNA adducts are repaired through nucleotide excision repair (NER) pathway. Due to extensive efforts, we now know a great deal about the mechanism of NER. Recognition of DNA damage is a critical step in the early stage of repair. Xeroderma pigmentosum group A complementing protein (XPA), replication protein A (RPA), XPC-hHR23B, and XPE can independently bind to damaged DNA. However, it is still in debate how the damage recognition proteins function at the damaged DNA site. We use biochemical and molecular approaches to analyze the role(s) of damage recognition proteins in the early stage of DNA repair. We are particularly interested in structural distortion of cisplatin-damaged DNA, a step essential for dual incision, but poorly understood.