Assistant Professor, Chemistry and Biochemistry-Med
Degrees and Appointments
- B.S., Physics 2002, University of North Texas
- M.S., Biology 2005, University of North Texas
- Ph.D., Biophysics 2010, University of Texas Southwestern Medical School
- Fellow 2014, University of Colorado Boulder
Awards and Honors
- National Research Service Award, 2012
- Al Gilman Award, 2009
- Leita Marsh Pharmacological Award, 2009
- National Research Service Award, 2006
Lou Gehrig's disease (amyotrophic lateral sclerosis, ALS) is a devastating neurodegenerative disease that results in the rapid onset of paralysis and death due to the death of upper and lower motor neurons. ALS affects 1:50,000 people per year and the average life expectancy is 3 years following diagnosis. The median age of onset is 55 years of age but it occurs in patients from their teenage years until late in life. Numerous genetic mutations have been shown to cause or closely associate with ALS over the past few years. Several of these mutations are in RNA-binding proteins. One such protein is FUS (also known as TLS). Like many of the genes that cause ALS, little is known about the wild type functions of this gene making it difficult to hypothesize the role this gene plays in disease pathology. FUS is the third leading known cause of ALS responsible for 5% of familial ALS and 1% of sporadic ALS. FUS is a nuclear protein but mutations in the nuclear localization signal of FUS are the predominant cause of ALS, which can lead to accumulation of the protein in the cytoplasm.
FUS is normally a nuclear protein (left). Some mutations in FUS (center) lead to little to no mislocalization of the protein to the cytoplasm. Other mutations (right) lead to some of the protein accumulating in the cytoplasm.
FUS binds RNA and forms fibrous protein assemblies (top). The purpose of these assemblies is to bind RNA Pol II to recruit the polymerase and aid in elongation. (bottom) FUS is an abundant nuclear protein that recognizes the immediate output of transcription, an RNA molecule, to trigger fibrous assembly formation near the transcription start sites of genes and regulate transcription.
Overview of FUS activity in the cell
FUS is one of the abundant factors bound to RNA Pol II in the nucleus. FUS binds to RNA Pol II and regulates transcription for thousands of genes. FUS binds the C-terminal domain (CTD) of RNA Pol II near the transcription start sites of genes. A loss of FUS leads to inappropriate phosphorylation of RNA Pol II at position Ser2 of the CTD. Also a loss of FUS leads to RNA Pol II accumulation at the transcription start sites of genes. This is because the polymerase fails to escape pausing and enter the active elongation phase of transcription.
The effect of ALS causing mutations on FUS activity
Mutations in FUS may lead to disease pathology either due to a loss of protein function or a gain of function or both. As a gain of function, FUS mislocalization to the cytoplasm by mutations in its nuclear localization signal could lead to toxicity. However, as noted above, some ALS causing mutations lead to little of any cytoplasmic accumulation of FUS protein. On the other hand, loss of FUS to the cytoplasm or aggregation of FUS may reduce the amount of active FUS in cells and thereby lead to a loss of FUS function. We discovered that although most FUS remains in the nucleus of ALS patient derived fibroblast cells, the protein is trapped in SDS-resistant aggregates. These aggregates reduce the amount of active protein in the cell. As with a FUS knockdown, inappropriate phosphorylation at Ser2 is observed for hundreds of genes. Additionally, the organization of active RNA Pol II is changed (above) both in a FUS knockdown (siFUS) and in ALS patient-derived cells (mFUS and ΔNLS).
Two translocation events (left) involving FUS and a FUS homologue, EWSR1, result in the formation of oncogenic fusion proteins that lead to Ewing sarcoma (EWSR1-Fli1) or myxoid liposarcoma (FLS-CHOP). These fusion proteins are proposed to act as transcription factors (right) by binding their target sequences, oligomerizing, and then recruiting RNA Pol II through interactions with the C-terminal domain of RNA Pol II.
The role of FET protein in cancer
FUS, EWSR1, and TAF15 compromise a group of homologous proteins known as the FET family of proteins. FUS and EWSR1 are involved in specific translocation events that lead to the development of specific tumors - myxoid liposarcoma and Ewing sarcoma, respectively. 85% of myxoid liposarcomas possess the FUS-CHOP translocation event. 90% of Ewing sarcomas posses the EWSR1-Fli1 translocation event. Myxoid liposarcomas are a tumor of the fatty tissues that typically occur in patients between the ages of 40 and 60. Ewing sarcomas are a primary bone cancer that usually occurs in children and adolescent. The mechanisms by which these oncogenes promote tumorigenesis is not well understood. Our lab is using Next-generation sequencing in both Ewing sarcomas cell lines and primary patient samples of Ewing sarcoma and myxoid liposarcomas, as well as characterization of the wild-type functions of EWSR1 and FUS, to develop an understanding how these fusion proteins contribute to tumorigenesis.
1. Schwartz JC, Podell ER, Han SSW, Berry JD, Eggan KC, Cech TR, "FUS is sequestered in nuclear aggregates in ALS patient fibroblasts" Mol Biol Cell, 2014; accepted
2. Schwartz JC, Wang X, Podell ER, Cech TR, "RNA seeds higher order assembly of FUS protein" Cell Reports, 2013; 5(4):918-25.
3. Schwartz JC, Ebmeier CC, Podell ER, Heimiller J, Taatjes DJ, Cech TR, "FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2" Genes Dev, 2012; 26:2690-95.
4. Pena-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff N, Tran TAT, Zou L, Xie X, Corey DR, Brugarolas J, "Reciprocal regulation of V-ATPases and mTORC1", EMBO J, 2011; 30(16):3242-58.
5. Schwartz JC, Corey DR, "Practical considerations for analyzing antigene RNAs (agRNAs): RNA immunoprecipitation of argonaute protein", Methods Mol Biol, 2011; 764:301-15.
6. Yue A, Schwartz JC, Younger ST, Chu Y, Gagnon KT, Elbashir S, Janowski BA, Corey DR, "Regulation of Transcription by Small RNAs Complementary to Sequences Downstream from the 3' Termini of Genes", Nat Chem Biol, 2010 Aug; 6(8):621-9.
7. Hu J, Matsui M, Gagnon KT, Schwartz JC, Gabillet S, Arar K, Wu J, Bezprozvanny I, Corey DR, "Inhibiting Expression of Mutant Huntingtin and Ataxin-3 by Targeting Expanded CAG Repeat RNAs", Nat Biotech, 2009 May; 27(5):478-84.
8. Schwartz, JC, Younger, S, Nguyen,N, Hardy, D, Monia, BP, Corey, DR, Janowski, BA, "Antisense Transcripts are Targets for Small Activating RNAs", Nat Struct Mol Biol. 2008 Aug;15(8):842-8.
9. Janowski BA, Huffman KE, Schwartz JC, Ram R, Nordsell R, Shames DS, Minna JD, Corey DR, "Involvement of AGO1 and AGO2 in mammalian transcriptional silencing", Nat Struct Mol Biol. 2006 Sep;13(9):787-92.
10. Janowski BA, Kaihatsu K, Huffman KE, Schwartz JC, Ram R, Hardy D, Mendelson CR, Corey DR, "Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids", Nat Chem Biol. 2005 Sep;1(4):210-5.
11. Janowski BA, Huffman KE, Schwartz JC, Ram R, Hardy D, Shames DS, Minna JS, Corey DR, "Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNA", Nat Chem Biol. 2005 Sep;1(4):216-22.