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Bryce M. Paschal

Bryce M. Paschal

Professor, Biochemistry and Molecular Genetics

Primary Location
Center for Signaling, West Complex-Room 7021
1400 Jefferson Park Ave, PO Box 800577
Charlottesville, VA 22908
Primary Phone Number
434.243.6521
Fax Number
434.924.1236
Email
[email protected]
Website
https://research.med.virginia.edu/cell-signaling/facilities/bryce-m-paschal/bryce-m-paschal-research-group/

Bio & Overview

My laboratory studies how nuclear transport and signal transduction control the compartmentalization and activity of transcription factors, particularly in the context of prostate cancer. A major focus of these studies is the androgen receptor (AR), a steroid hormone receptor that is critical for prostate cell growth. Translocation of AR through the nuclear pore complex (NPC) relies on features common to most nuclear transport pathways: (i) the use of nuclear import or export signals; (ii) the recognition of these signals by receptors that mediate translocation through the NPC; and (iii) RanGTPase-dependent assembly and disassembly of transport complexes. The signals that specify nuclear import and export of AR, the receptors that mediate AR translocation, and the role of the RanGTPase in AR transport are all under investigation in my laboratory. Nuclear export would be expected to provide an effective mechanism for terminating the transcriptional response to androgen, however, we have recently found that AR translocation to the cytoplasm is important for its activity in the nucleus. This apparent paradox may reflect an undefined step in AR maturation, or crosstalk between AR and signal transduction pathways in the cytoplasm. AR is the target of multiple kinases, and we have generated phosphosite antibodies to study the pathways and functions of phospho-regulation. In the course of these studies we discovered a novel mechanism for loading protein phosphatase 2A (PP2A) onto AR. The loading mechanism requires small t antigen, a product encoded by SV40 that binds and alters the structure of a PP2A subunit. Current experiments are aimed at defining the structural basis of the PP2A loading reaction, as well as determining the cellular factors that mediate PP2A loading onto AR in untransformed cells. While biochemical analysis is the cornerstone of our nuclear transport and signal transduction studies, we also employ cell biological approaches including microinjection, fluorescence microscopy and real-time imaging in live cells, and animal models of tumorigenesis. Our studies benefit from ongoing collaborations with groups that specialize in mass spectrometry, pathology, and prostate cancer.

Academic Information

Department
Biochemistry and Molecular Genetics
Academic Title
Professor

Primary Education

  • BA, Biology, University of North Carolina, Chapel Hill, NC, 1982
  • PhD, Medical Science, University of Massachusetts Medical School, MA, 1992
  • Postdoc, Cell Biology, The Scripps Research Institute, La Jolla, CA, 1996

Other Appointments

  • Pathology
  • Professor, MII
  • Professor, BMBG
  • Professor, MCDB

Other Affiliations

  • Member, Molecular Genetics and Epigenetics Program
  • MSTP
  • Professor, BIMS

Research Interests

Nuclear Transport, Signaling, and Cancer

Research Disciplines

  • Biochemistry
  • Cancer Biology

Research Opportunities

  • Biochemistry
  • Cancer Biology

PhD Programs

  • Biochemistry & Molecular Genetics
  • Experimental Pathology

Selected Publications

2023

Vela-Rodríguez, C., Yang, C., Alanen, H. I., Eki, R., Abbas, T. A., Maksimainen, M. M., . . . Lehtiö, L. (2023). Oligomerisation mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.. bioRxiv. doi:10.1101/2023.11.29.569193

Yang, C., Wierbilowicz, K., Dworak, N. M., Bae, S. Y., Tengse, S. B., Abianeh, N., . . . Paschal, B. M. (2023). Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells. CANCER RESEARCH COMMUNICATIONS, 3(4), 592-606. doi:10.1158/2767-9764.CRC-23-0086

2022

Ashok, Y., Vela-Rodriguez, C., Yang, C., Alanen, H. I., Liu, F., Paschal, B. M., & Lehtio, L. (2022). Reconstitution of the DTX3L PARP9 complex reveals determinants for high-affinity heterodimerization and multimeric assembly. BIOCHEMICAL JOURNAL, 479(3), 289-304. doi:10.1042/BCJ20210722

2021

Sienkiewicz, K., Yang, C., Paschal, B. M., & Ratan, A. (2022). Genomic analyses of the metastasis-derived prostate cancer cell lines LNCaP, VCaP, and PC3-AR. PROSTATE, 82(4), 442-451. doi:10.1002/pros.24290

Luscher, B., Ahel, I., Altmeyer, M., Ashworth, A., Bai, P., Chang, P., . . . Ziegler, M. (2022). ADP-ribosyltransferases, an update on function and nomenclature. FEBS JOURNAL, 289(23), 7399-7410. doi:10.1111/febs.16142

Kamata, T., Yang, C. -S., & Paschal, B. M. (2021). PARP7 mono-ADP-ribosylates the agonist conformation of the androgen receptor in the nucleus. BIOCHEMICAL JOURNAL, 478(15), 2999-3014. doi:10.1042/BCJ20210378

Yang, C. -S., Jividen, K., Kamata, T., Dworak, N., Oostdyk, L., Remlein, B., . . . Paschal, B. M. (2021). Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly. NATURE COMMUNICATIONS, 12(1). doi:10.1038/s41467-021-23055-6

Kamata, T., Yang, C. -S., Melhuish, T. A., Frierson Jr., H. F., Wotton, D., & Paschal, B. M. (2021). Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling. CELLS, 10(2). doi:10.3390/cells10020363

2020

Costa-Pinheiro, P., Heher, A., Raymond, M. H., Jividen, K., Shaw, J. J. P., Paschal, B. M., . . . Kester, M. (2020). Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling. ISCIENCE, 23(12). doi:10.1016/j.isci.2020.101855

Oostdyk, L. T., Wang, Z., Zang, C., Li, H., McConnell, M. J., & Paschal, B. M. (2020). An epilepsy-associated mutation in the nuclear import receptor KPNA7 reduces nuclear localization signal binding. SCIENTIFIC REPORTS, 10(1). doi:10.1038/s41598-020-61369-5

2019

Oostdyk, L. T., McConnell, M. J., & Paschal, B. M. (2019). Characterization of the Importin-β binding domain in nuclear import receptor KPNA7. BIOCHEMICAL JOURNAL, 476, 3413-3434. doi:10.1042/BCJ20190717

Paschal, B. M. (2019). Methods in Nuclear Architecture and Transport Introduction. METHODS, 157, 1-2. doi:10.1016/j.ymeth.2019.02.020

Kamata, T., Yang, C. -S., Jividen, K., Spencer, A., Dworak, N., Oostdyk, L. T., & Paschal, B. M. (2019). Detection of ADP-Ribosylation of the Androgen Receptor Using the Recombinant Macrodomain AF1521 from Archaeoglobus fulgidus. NUCLEAR RECEPTORS: METHODS AND EXPERIMENTAL PROTOCOLS, 1966, 107-124. doi:10.1007/978-1-4939-9195-2_9

2018

Dworak, N., Makosa, D., Chatterjee, M., Jividen, K., Yang, C. -S., Snow, C., . . . Paschal, B. M. (2019). A nuclear lamina-chromatin-Ran GTPase axis modulates nuclear import and DNA damage signaling. AGING CELL, 18(1). doi:10.1111/acel.12851

Kelley, J. B., & Paschal, B. M. (2019). Fluorescence-based quantification of nucleocytoplasmic transport. METHODS, 157, 106-114. doi:10.1016/j.ymeth.2018.11.002

Oostdyk, L. T., Shank, L., Jividen, K., Dworak, N., Sherman, N. E., & Paschal, B. M. (2019). Towards improving proximity labeling by the biotin ligase BirA. METHODS, 157, 66-79. doi:10.1016/j.ymeth.2018.11.003

Yang, J., Wei, X., Tufan, T., Kuscu, C., Unlu, H., Farooq, S., . . . Adli, M. (2018). Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. GENOME BIOLOGY, 19. doi:10.1186/s13059-018-1572-4

Jividen, K., Kedzierska, K. Z., Yang, C. -S., Szlachta, K., Ratan, A., & Paschal, B. M. (2018). Genomic analysis of DNA repair genes and androgen signaling in prostate cancer. BMC CANCER, 18. doi:10.1186/s12885-018-4848-x

2017

Yang, C. -S., Melhuish, T. A., Spencer, A., Ni, L., Hao, Y., Jividen, K., . . . Paschal, B. M. (2017). The protein kinase C super-family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression. PROSTATE, 77(15), 1452-1467. doi:10.1002/pros.23400

Yang, C. -S., Jividen, K., Spencer, A., Dworak, N., Ni, L., Oostdyk, L. T., . . . Paschal, B. M. (2017). Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9. MOLECULAR CELL, 66(4), 503-+. doi:10.1016/j.molcel.2017.04.028

2015

Zboray, L., Pluciennik, A., Curtis, D., Liu, Y., Berman-Booty, L. D., Orr, C., . . . Merry, D. E. (2015). Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA. CELL REPORTS, 13(10), 2312-2323. doi:10.1016/j.celrep.2015.11.019

Hansen, J., Snow, C., Tuttle, E., Ghoneim, D. H., Yang, C. -S., Spencer, A., . . . Paciorkowski, A. R. (2015). De Novo Mutations in SIK1 Cause a Spectrum of Developmental Epilepsies. AMERICAN JOURNAL OF HUMAN GENETICS, 96(4), 682-690. doi:10.1016/j.ajhg.2015.02.013

2014

Chatterjee, M., & Paschal, B. M. (2015). Disruption of the Ran System by Cysteine Oxidation of the Nucleotide Exchange Factor RCC1. MOLECULAR AND CELLULAR BIOLOGY, 35(3), 566-581. doi:10.1128/MCB.01133-14

Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., . . . Theodorescu, D. (2014). Discovery and characterization of small molecules that target the GTPase Ral. NATURE, 515(7527), 443-+. doi:10.1038/nature13713

Datta, S., Snow, C. J., & Paschal, B. M. (2014). A pathway linking oxidative stress and the Ran GTPase system in progeria. MOLECULAR BIOLOGY OF THE CELL, 25(8), 1202-1215. doi:10.1091/mbc.E13-07-0430

Chatterjee, M., & Paschal, B. M. (2014). Oxidative Stress Disrupts the Ran System Through Reversible Modification of Cysteine Residues in RCC1.. MOLECULAR BIOLOGY OF THE CELL, 25. Retrieved from https://www.webofscience.com/

Snow, C. J., & Paschal, B. M. (2014). Roles of the Nucleoporin Tpr in Cancer and Aging. CANCER BIOLOGY AND THE NUCLEAR ENVELOPE: RECENT ADVANCES MAY ELUCIDATE PAST PARADOXES, 773, 309-322. doi:10.1007/978-1-4899-8032-8_14

Bjerke, G. A., Pietrzak, K., Melhuish, T. A., Frierson, H. F. J., Paschal, B. M., & Wotton, D. (2014). Prostate Cancer Induced by Loss of Apc Is Restrained by TGFβ Signaling. PLOS ONE, 9(3). doi:10.1371/journal.pone.0092800

2013

Ni, L., Llewellyn, R., Kesler, C. T., Kelley, J. B., Spencer, A., Snow, C. J., . . . Paschal, B. M. (2013). Androgen Induces a Switch from Cytoplasmic Retention to Nuclear Import of the Androgen Receptor. MOLECULAR AND CELLULAR BIOLOGY, 33(24), 4766-4778. doi:10.1128/MCB.00647-13

Paciorkowski, A. R., Weisenberg, J., Kelley, J. B., Spencer, A., Tuttle, E., Ghoneim, D., . . . Paschal, B. M. (2014). Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation. EUROPEAN JOURNAL OF HUMAN GENETICS, 22(5), 587-593. doi:10.1038/ejhg.2013.196

Bjerke, G. A., Yang, C. -S., Frierson, H. F., Paschal, B. M., & Wotton, D. (2014). Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. ONCOGENE, 33(28), 3660-3667. doi:10.1038/onc.2013.342

Snow, C. J., Dar, A., Dutta, A., Kehlenbach, R. H., & Paschal, B. M. (2013). Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport. JOURNAL OF CELL BIOLOGY, 201(4), 541-557. doi:10.1083/jcb.201212117

Sun, D., Layer, R., Mueller, A. C., Cichewicz, M. A., Negishi, M., Paschal, B. M., & Dutta, A. (2014). Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells. ONCOGENE, 33(11), 1448-1457. doi:10.1038/onc.2013.77

2011

Gioeli, D., & Paschal, B. M. (2012). Post-translational modification of the androgen receptor. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 352(1-2), 70-78. doi:10.1016/j.mce.2011.07.004

Kelley, J. B., Datta, S., Snow, C. J., Chatterjee, M., Ni, L., Spencer, A., . . . Paschal, B. M. (2011). The Defective Nuclear Lamina in Hutchinson-Gilford Progeria Syndrome Disrupts the Nucleocytoplasmic Ran Gradient and Inhibits Nuclear Localization of Ubc9. MOLECULAR AND CELLULAR BIOLOGY, 31(16), 3378-3395. doi:10.1128/MCB.05087-11

2010

Kelley, J. B., Talley, A. M., Spencer, A., Gioeli, D., & Paschal, B. M. (2010). Karyopherin α7 (KPNA7), a divergent member of the importin α family of nuclear import receptors. BMC CELL BIOLOGY, 11. doi:10.1186/1471-2121-11-63

Braddock, S. R., Ardinger, H. H., Yang, C. -S., Paschal, B. M., & Hall, B. D. (2010). Petty Syndrome and Fontaine-Farriaux Syndrome: Delineation of a Single Syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 152A(7), 1718-1723. doi:10.1002/ajmg.a.33468

Ni, L., Yang, C. -S., Gioeli, D., Frierson, H., Toft, D. O., & Paschal, B. M. (2010). FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells. MOLECULAR AND CELLULAR BIOLOGY, 30(5), 1243-1253. doi:10.1128/MCB.01891-08