The C-Terminal SynMuv/DdDUF926 Domain Regulates the Function of the N-Terminal Domain of DdNKAP

Burgute, Bhagyashri D.; Peche, Vivek S.; Müller, Rolf; Matthias, Jan; Gassen, Berthold; Eichinger, Ludwig M.; Glöckner, Gernot; Noegel, Angelika A.

doi:10.1371/journal.pone.0168617

Cited by 4 publications

(3 citation statements)

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“…Instead, it demonstrates that an association with HDAC3 is critical for NKAP function in some cell types but not others. It is also important to note that Y352 and F347 in NKAP, which are critical for its association with HDAC3, as well as several surrounding residues, are perfectly conserved in NKAP orthologs across all species that have NKAP, including mammals, Drosophila, Dictyostelium, and Arabidopsis (19). Hence, determining the biological consequence of disrupting this region of NKAP serves to critically evaluate the significance of this evolutionary conservation.…”

Section: Discussionmentioning

confidence: 99%

NKAP Must Associate with HDAC3 to Regulate Hematopoietic Stem Cell Maintenance and Survival

Shapiro

Lehrke

Chung

et al. 2019

The Journal of Immunology

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NKAP is a multifunctional nuclear protein that associates with the histone deacetylase HDAC3. Although both NKAP and HDAC3 are critical for hematopoietic stem cell (HSC) maintenance and survival, it was not known whether these two proteins work together. To assess the importance of their association in vivo, serial truncation and alanine scanning was performed on NKAP to identify the minimal binding site for HDAC3. Mutation of either Y352 or F347 to alanine abrogated the association of NKAP with HDAC3, but did not alter NKAP localization or expression. Using a linked conditional deletion/re-expression system in vivo, we demonstrated that re-expression of the Y352A NKAP mutant failed to restore HSC maintenance and survival in mice when endogenous NKAP expression was eliminated using Mx1-cre and poly-IC, whereas re-expression of wild type NKAP maintained the HSC pool. However, Y352A NKAP did restore proliferation in murine embryonic fibroblasts when endogenous NKAP expression was eliminated using ER-cre and tamoxifen. Therefore, Y352 in NKAP is critical for association with HDAC3 and for HSC maintenance and survival but is not important for proliferation of murine embryonic fibroblasts, demonstrating that NKAP functions in different complexes in different cell types.

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Section: Discussionmentioning

confidence: 99%

NKAP Must Associate with HDAC3 to Regulate Hematopoietic Stem Cell Maintenance and Survival

Shapiro

Lehrke

Chung

et al. 2019

The Journal of Immunology

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“…(Hennen et al, 2018), as well as interact with other components (e.g. DdNKAP, Burgute et al, 2016, or NE81 Batsios et al, 2016a. Connectivity to Sun1 or an underlying nuclear network may serve a couple of important functions.…”

Section: The Dynamics Of the Nuclear Envelope During Mitosismentioning

confidence: 99%

Nuclear envelope organization in Dictyostelium discoideum

Batsios¹,

Gräf²,

Koonce³

et al. 2019

Int. J. Dev. Biol.

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The nuclear envelope consists of the outer and the inner nuclear membrane, the nuclear lamina and the nuclear pore complexes, which regulate nuclear import and export. The major constituent of the nuclear lamina of Dictyostelium is the lamin NE81. It can form filaments like B-type lamins and it interacts with Sun1, as well as with the LEM/HeH-family protein Src1. Sun1 and Src1 are nuclear envelope transmembrane proteins involved in the centrosome-nucleus connection and nuclear envelope stability at the nucleolar regions, respectively. In conjunction with a KASH-domain protein, Sun1 usually forms a so-called LINC complex. Two proteins with functions reminiscent of KASH-domain proteins at the outer nuclear membrane of Dictyostelium are known; interaptin which serves as an actin connector and the kinesin Kif9 which plays a role in the microtubule-centrosome connector. However, both of these lack the conserved KASH-domain. The link of the centrosome to the nuclear envelope is essential for the insertion of the centrosome into the nuclear envelope and the appropriate spindle formation. Moreover, centrosome insertion is involved in permeabilization of the mitotic nucleus, which ensures access of tubulin dimers and spindle assembly factors. Our recent progress in identifying key molecular players at the nuclear envelope of Dictyostelium promises further insights into the mechanisms of nuclear envelope dynamics. , and build upon the material for any purpose, even commercially), providing you give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. Printed in Spain Abbreviations used in this paper: BAF, barrier to autointegration factor; BioID, proximity-dependent biotin identification; CDK1, cyclin-dependent kinase 1; cryo-ET, cryo-electron tomography; DAPI, 4′,6-diamidin-2-phenylindol; EM, electron microscopy; ER, endoplasmic reticulum; ExM, expansion microscopy; feSEM, field-emission scanning electron microscopy; FRAP, fluorescence recovery after photobleaching; GFP, green fluorescent protein; HeH, helix-extension-helix; IF, intermediate filament; INM, inner nuclear membrane; KASH, Klarsicht, ANC-1, Syne Homology; LBR, lamin B receptor; LECA, last eukaryotic common ancestor; LEM, lamina-associated polypeptide 2 (LAP2), Emerin, and MAN1; LINC, linker of the nucleoskeleton and the cytoskeleton; MCAK, mitotic centromere-associated kinesin; MEF, mouse embryonic fibroblast; NET, nuclear envelope transmembrane protein; NLS, nuclear localization sequence; NPC, nuclear pore complex; ONM, outer nuclear membrane; STED, stimulated emission depletion. import and export. On its nuclear side, the INM is associated with a fibrous, so-called nuclear lamina. Among the NETs, the Sun-domain proteins in the INM (e.g. Sun1) and KASH-domain proteins in the ONM (e.g. nesprin) have to be highlighted, as they form the so-called LINC complex, which spans the whole nuclear envelope (Lee and Burke, 2018...

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“…Homozygous loss of classical splicing factors often leads to embryonic lethality in mammalian and other systems, making the in vivo functional study of these factors more challenging. NF-kappaB-activating protein (NKAP) family proteins are a class of SR-related proteins highly conserved across different species ( Burgute et al., 2014 , 2016 ). Genetic and biochemical studies have revealed their important functions in various biological processes, including cell proliferation and apoptosis ( Pajerowski et al., 2009 , 2010 ; Hsu et al., 2011 ; Sanchez-Garcia et al., 2015 ; Thapa et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

Guo,

Miao,

Liu

et al. 2023

Journal of Molecular Cell Biology

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Mutations or dysregulated expression of NF-kappaB activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes changes in cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

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The C-Terminal SynMuv/DdDUF926 Domain Regulates the Function of the N-Terminal Domain of DdNKAP

Cited by 4 publications

References 53 publications

NKAP Must Associate with HDAC3 to Regulate Hematopoietic Stem Cell Maintenance and Survival

NKAP Must Associate with HDAC3 to Regulate Hematopoietic Stem Cell Maintenance and Survival

Nuclear envelope organization in Dictyostelium discoideum

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

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