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Natalie Leach


leachnr@gmail.com
Mentor: Richard Roller, Ph.D.
Lab Room: 3-401 BSB
Lab Phone: 319-335-7664

The nuclear lamina is fibrous mesh made of lamin proteins connected with the inner nuclear membrane (INM) through associations with integral membrane proteins. The lamina gives the nucleus its shape. The integral membrane proteins that anchor the lamins to the INM are known as lamin associated proteins (LAPs) which include emerin, LAP2, Lamin B Receptor (LBR), and MAN1, all of which have lamin binding domains. The lamins and LAPs play roles in nuclear assembly, gene regulation, and DNA replication through interactions with chromatin, transcription and cell-cycle regulation proteins. Herpes Simplex Virus type 1 (HSV-1) is an enveloped double-stranded DNA virus. After replication and capsid assembly in the nucleus, the capsids attach to the INM where it is wrapped around the capsid. The INM is then pinched off forming enveloped particle in the perinuclear space. The enveloped viral particle then fuses with outer nuclear membrane and is released into the cytosol. It has been hypothesized that in order for the capsid to access the inner nuclear membrane, the lamina must be disrupted. It is possible that the virus could mimic or hijack the cellular mechanisms for disrupting the lamina. During mitosis, the lamina is disassembled and reassembled. Cellular kinases such as Protein Kinase C (PKC), cdc2 kinase, and cyclic-AMP-dependant kinase (PKA) disrupt the lamina during mitosis through phosphorylation of lamins and LAPs. My work focuses on evaluating the hypothesis that HSV-1 proteins may induce phosphorylation of lamins and LAPs to disrupt the lamina to allow for primary envelopment at the INM. In addition to disrupting the structure of the lamina, viral protein association with lamins or LAPs could also play a role in regulation of viral or cellular gene expression during infection.

Leach NR, Roller RJ. Inhibition of PKC isoforms blocks efficient replication and nuclear egress of herpes simplex type 1. In Press. Accepted July 2, 2010. Virology.

Leach N, Bjerke SL, Christensen DK, Bouchard JM, Mou F, Park R, Baines J, Haraguchi T, Roller RJ. Emerin is hyperphosphorylated and redistributed in herpes simplex virus type 1-infected cells in a manner dependent on both UL34 and US3. J Virol. 2007 Oct;81(19):10792-803. Epub 2007 Jul 25. PMCID: PMC2045475 PMID: 17652388

Abstracts

Bjerke SL, Leach N, Christensen D, Roller R. International Herpes Workshop: HSV-1 Infection Alters the Localization Modification of Lamin-Associated Proteins Emerin and LAP2 in a UL34 and US3-dependent Manner. Poster presentation. International Herpes Workshop. Seattle, WA.

Leach N, Roller RJ. Hsv-1 Infection Alters The Modification Of The Lamin-Associated Protein Emerin In An Ul34, Us3, And Pkcδ-Dependent Manner. Poster presentation. International Herpes Workshop. Asheville, NC, 2007.

Leach N, Roller RJ. Inhibition Of Protein Kinase C Delta Suggests Role In Hsv-1 Nuclear Egress And Lamin Associated Protein Disruption. Poster presentation. FASEB Virus Structure and Assembly. Saxtons River, VT, 2008.



Honors and Awards

  • 2006 MCB Retreat Travel Award for Poster Presentation
  • 2009 MCB Retreat Travel Award for Poster Presentation