The overall goal of this proposal is to understand at a molecular level the functions of the RAN GTPase, and of Ran-interacting proteins, in nuclear protein import and export. This goal will be approached via the following specific aims: 1. Critically test the hypothesis that Ran enters and exits the nucleus as a component of the transport receptor complex. 2. Examine central aspects of the transport mechanism: determine whether nuclear Ran:GTP is the only energy source required for import and export; and test the hypothesis that Ran binding to RanBP2 is a necessary step in nuclear protein import. 3. Determine whether the Ran binding protein, RanBP1, shuttles in and out of the nucleus, and functions as a chaperone for importin-beta export. 4. Identify the novel nuclear import signal on Hrb3, a new Ran binding protein, and clone the receptor for this signal. These goals will be achieved using a variety of technologies including micro-injection of recombinant proteins and in vitro transport assays. Nuclear transport is a key regulatory step in signal transduction pathways that modulate gene expression and the cell cycle. Nuclear transport is also targetted by several clinically- important viruses, such as HIV, to ensure preferential replication of the viral genome, and synthesis of new virions. Understanding the detailed mechanism of nuclear protein transport may therefore provide novel targets for anti-viral therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050526-09
Application #
6519568
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Anderson, Richard A
Project Start
1994-08-01
Project End
2003-05-31
Budget Start
2002-04-01
Budget End
2003-05-31
Support Year
9
Fiscal Year
2002
Total Cost
$304,455
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Andrews, Alex M; McCartney, Heather J; Errington, Tim M et al. (2018) A senataxin-associated exonuclease SAN1 is required for resistance to DNA interstrand cross-links. Nat Commun 9:2592
Rodriguez-Boulan, Enrique; Macara, Ian G (2014) Organization and execution of the epithelial polarity programme. Nat Rev Mol Cell Biol 15:225-42
Petkowski, Janusz J; Bonsignore, Lindsay A; Tooley, John G et al. (2013) NRMT2 is an N-terminal monomethylase that primes for its homologue NRMT1. Biochem J 456:453-62
Errington, Timothy M; Macara, Ian G (2013) Depletion of the adaptor protein NCK increases UV-induced p53 phosphorylation and promotes apoptosis. PLoS One 8:e76204
Bailey, Aaron O; Panchenko, Tanya; Sathyan, Kizhakke M et al. (2013) Posttranslational modification of CENP-A influences the conformation of centromeric chromatin. Proc Natl Acad Sci U S A 110:11827-32
Petkowski, Janusz J; Schaner Tooley, Christine E; Anderson, Lissa C et al. (2012) Substrate specificity of mammalian N-terminal ?-amino methyltransferase NRMT. Biochemistry 51:5942-50
Tooley, Christine E Schaner; Petkowski, Janusz J; Muratore-Schroeder, Tara L et al. (2010) NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein. Nature 466:1125-8
Eisinger-Mathason, T S Karin; Andrade, Josefa; Groehler, Angela L et al. (2008) Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. Mol Cell 31:722-36
Hao, Yi; Macara, Ian G (2008) Regulation of chromatin binding by a conformational switch in the tail of the Ran exchange factor RCC1. J Cell Biol 182:827-36
Dorfman, Julia; Macara, Ian G (2008) STRADalpha regulates LKB1 localization by blocking access to importin-alpha, and by association with Crm1 and exportin-7. Mol Biol Cell 19:1614-26

Showing the most recent 10 out of 38 publications