University of South Florida
College of Arts and Sciences
Contribute to our future
Office: BSF 216
Lab: BSF 262, 264
Email: ykee (at) usf.edu
2005: A.P. Bradie Endowed Golden Research Award (UT-Austin)
2006: Outstanding Teaching Award (UT-Austin)
2008-2011: Career Development Fellowship, Leukemia and Lymphoma Society
2008: Honor Award, Leukemia and Lymphoma Society Naming Program in the Field of Blood cancer Research
2014: USF New Researcher Grant
2014: USF Proposal Enhancement Grant
2014: Moffitt-American Cancer Society Institutional Grant
2015-NIH R15NIH RO1
Genome stability, DNA damage repair, Ubiquitin and proteolysis, tumor suppressive mechanisms
Safeguarding genomic integrity from genotoxic stresses is critical for biology of a cell. DNA repair or DNA damage responses are under sophisticated controls that must be accurately and rapidly executed, when the genome integrity is challenged. Understanding the molecular regulation of DNA damage response factors that promote genome stability is a significant subject for basic biological perspective as well as clinical aspects. Our lab studies molecular mechanisms of maintaining genome integrity, by studying the functions of proteins involved in DNA damage response and DNA repair. Below are the main areas we are currently focusing on:
DNA damage response is a concerted action of numerous mechanisms that ensure to minimize genomic error. Among the mechanisms is a temporary suppression of transcription at the damaged lesions. Failure in such mechanism can compromise genomic integrity through faulty RNA synthesis or interruption of DNA repair, which could lead to tumorigenesis or other disorders. BMI1 and RNF2, core components of Polycomb-Repressive Complex 1, are critical for regulating epigenetic gene silencing during organismal development and maintaining stem cell homeostasis. Evidence also suggests that BMI1 is implicated in DNA damage response in differentiated cells, possibly suggesting that their gene silencing activity may have been co-opted to preserve genomic integrity. We are studying how transcriptional silencing is regulated during DNA damage response, by new protein network we identified that controls FACT histone chaperone (below figure). Our hypothesis is that these factors are important for transcriptional repression at lesions and consequently for preventing replication stress and tumor formation. We are using genetic, biochemical analysis to characterize the OTUD5-UBR5-FACT complex and their potential relationship with BMI1-RNF2 in gene silencing. We also study the possible roles of histone ubiquitination in gene expression regulation as well as in DNA repair.
Fanconi Anemia (FA) is a genomic instability disorder that is associated with defective DNA repair activities. FA individuals display congenital anomaly, bone marrow disorder, and increased cancer incidence. At the cellular level, FA cells show hypersensitivity to DNA damaging agents such as Cisplatin and Mitomycin C. There are currently 19 FA subtypes (FANCA ~ FANCT) identified, whose gene products are believed to function in a common pathway that coordinate and execute DNA repair activities. Presence of such large number of protein subgroups that give rise to FA underscores the complex genetics of the disease and presents FA as an important model disease to study how DNA repair activities are executed in response to genotoxic insults. One of the underlying molecular events defective in the FA cells is monoubiquitination of FANCD2 protein by a group of nuclear FA proteins (FANC-A, B, C, E, F, G, L, and M) that function as an E3 ubiquitin ligase. The monoubiquitinated FANCD2 functionally interacts with other DNA repair proteins, such as RAD51 DNA homologous recombination (HR) repair factor, or nucleases FAN1 and CtIP, to facilitate DNA repair pathways in response to various genotoxic stresses. We are interested in understanding the regulation and function of FANCD2 monoubiquitination, as well as the functional interplay between the FA proteins and the canonical HR repair proteins.
The ubiquitin-proteasome system (UPS) is an essential regulatory mechanism for promoting genome stability. Deubiquitinating enzymes (DUBs), integral components of the UPS, have emerged as key players in the maintenance of the genome stability. Our lab particularly studies function and regulation of DUBs in promoting DNA repair activities in human cells.
For these projects, we use a range of modern molecular biology tools that include mammalian cell culture, RNAi, gene knockouts, confocal microscopy, and mass spectrometry analysis.
Angelo De Vivo, Dante Deascanis, Justin Fletcher, Anthony Sanchez, Neysha Tirado-Class