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MKRN2 Interacts with GLE1 and Negati...

Wolf, Eric J.

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MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development.

Record Type:	Electronic resources : Monograph/item
Title/Author:	MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development./
Author:	Wolf, Eric J.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	149 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
Contained By:	Dissertations Abstracts International81-05B.
Subject:	Molecular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=22624840
ISBN:	9781392600559

MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development.
Wolf, Eric J.

MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 149 p.

Source: Dissertations Abstracts International, Volume: 81-05, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item must not be sold to any third party vendors.

Canonical mammalian mRNA export is terminated at the cytoplasmic face of the nuclear pore complex. A key factor implicated in mRNA export termination is GLE1, a highly conserved, DEAD-box helicase activator protein. I conducted an affinity-purification mass-spectrometry screen of human RNA-binding E3 ubiquitin ligases from tissue cell cultures, and discovered a novel physical interaction between MKRN2 and a GLE1-containing complex of mRNA export factors. We next assessed GLE1 epistasis with MKRN2 in a genetically tractable zebrafish model. Consistent with an antagonistic relationship between GLE1 and MKRN2, injection of GLE1 morpholinos into zebrafish embryos deficient in MKRN2 rescued or altered the pronounced retinal defects associated with GLE1 depletion. My data therefore implicate MKRN2 as both a novel macromolecular binding partner and putative new negative regulator of GLE1, and by extension mRNA export. To further explore this hypothesis, I subsequently investigated the function of MKRN2 in mRNA processing in human cell lines. Analysis of the RNA-binding activity of MKRN2 by individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) established that MKRN2 binds to specific mRNAs directly and predominantly in their 3' untranslated region (3'UTR) in regions enriched for C-rich sequences. Biochemical fractionation and sequencing of transcripts from MKRN2 knockdown cells also revealed that nuclear export of mRNAs bound by MKRN2 was enhanced upon MKRN2 knockdown. Taken together, these results indicate that MKRN2 interacts physically and functionally with GLE1, and other associated widely conserved mRNA export factors, to negatively regulate mRNA export of select target transcripts.

ISBN: 9781392600559Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

GLE1

MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development.
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100 1 $a Wolf, Eric J. $3 3550247
245 1 0 $a MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2019
300 $a 149 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
500 $a Advisor: Emili, Andrew.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2019.
506 $a This item must not be sold to any third party vendors.
520 $a Canonical mammalian mRNA export is terminated at the cytoplasmic face of the nuclear pore complex. A key factor implicated in mRNA export termination is GLE1, a highly conserved, DEAD-box helicase activator protein. I conducted an affinity-purification mass-spectrometry screen of human RNA-binding E3 ubiquitin ligases from tissue cell cultures, and discovered a novel physical interaction between MKRN2 and a GLE1-containing complex of mRNA export factors. We next assessed GLE1 epistasis with MKRN2 in a genetically tractable zebrafish model. Consistent with an antagonistic relationship between GLE1 and MKRN2, injection of GLE1 morpholinos into zebrafish embryos deficient in MKRN2 rescued or altered the pronounced retinal defects associated with GLE1 depletion. My data therefore implicate MKRN2 as both a novel macromolecular binding partner and putative new negative regulator of GLE1, and by extension mRNA export. To further explore this hypothesis, I subsequently investigated the function of MKRN2 in mRNA processing in human cell lines. Analysis of the RNA-binding activity of MKRN2 by individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) established that MKRN2 binds to specific mRNAs directly and predominantly in their 3' untranslated region (3'UTR) in regions enriched for C-rich sequences. Biochemical fractionation and sequencing of transcripts from MKRN2 knockdown cells also revealed that nuclear export of mRNAs bound by MKRN2 was enhanced upon MKRN2 knockdown. Taken together, these results indicate that MKRN2 interacts physically and functionally with GLE1, and other associated widely conserved mRNA export factors, to negatively regulate mRNA export of select target transcripts.
590 $a School code: 0779.
650 4 $a Molecular biology. $3 517296
650 4 $a Biochemistry. $3 518028
650 4 $a Developmental biology. $3 592588
653 $a GLE1
653 $a MKRN2
653 $a mRNA export
653 $a Retinal development
653 $a RNA binding protein
690 $a 0307
690 $a 0487
690 $a 0758
710 2 $a University of Toronto (Canada). $b Molecular and Medical Genetics. $3 3177543
773 0 $t Dissertations Abstracts International $g 81-05B.
790 $a 0779
791 $a Ph.D.
792 $a 2019
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=22624840