The KRAB Zinc Finger Gene   Encodes an RNA-binding Protein Tightly Associated with the Nuclear Matrix

Grondin, Benoı̂t; Bazinet, Martine; Aubry, Muriel

doi:10.1074/jbc.271.26.15458

Cited by 59 publications

(80 citation statements)

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“…This result suggests that, in addition to its potential function in transcriptional regulation, ZNF74 may also be involved in RNA metabolism. We also previously reported that ZNF74 is tightly associated with the nuclear matrix, since detergent, DNase, RNase, and high salt treatments could not release it from this nuclear scaffold structure (15). In this study, we report that the ZNF74 zinc finger domain acts as a nuclear matrix targeting sequence.…”

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confidence: 61%

“…Although the presence of a KRAB motif and of 12 Cys 2 -His 2 zinc finger motifs suggest that ZNF74 may function as a transcription factor, we recently demonstrated that its zinc finger domain harbors an RNA binding activity in vitro (15). This result suggests that, in addition to its potential function in transcriptional regulation, ZNF74 may also be involved in RNA metabolism.…”

mentioning

confidence: 88%

“…pMAL-c vector (New England Biolabs) was used to generate maltosebinding protein (MBP) fusion constructs for expression in Escherichia coli. The following constructs were previously described in Grondin et al (15): HA-ZNF74-(1-572), HA-ZNF74⌬Krab-(68 -572), HA-N⌬Krab-Zn-(68 -509), HA-Zn-C-(175-572), HA-Zn-(175-509), MBP-ZNF74-(1-572), MBP-ZNF74-(106 -572), MBP-Zn-(175-509), and MBP-␤-gal-␣ (also called MBP herein). GAL4 DNA binding domain (GAL4-(1-147)) fusion proteins were obtained by introducing either the zinc finger domain (aa 175-509) or the N-terminal domain (aa 1-174) of ZNF74 in a Rous sarcoma virus enhancer-driven eukaryotic expression vector pRSVGAL4 (kindly provided by Dr. Robert Rehfuss).…”

Section: Methodsmentioning

confidence: 99%

“…We previously cloned ZNF74, a gene that encodes a KRAB/ Cys 2 -His 2 protein (15). ZNF74 lies a few kilobases proximal to a polymorphic CA repeat (D22S264) (16) that was shown to be a distal marker for 22q11.2 deletions associated with increased susceptibility to schizophrenia (17).…”

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confidence: 99%

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Direct Interaction of the KRAB/Cys2-His2Zinc Finger Protein ZNF74 with a Hyperphosphorylated Form of the RNA Polymerase II Largest Subunit

Grondin

Côté

Bazinet

et al. 1997

Journal of Biological Chemistry

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We previously identified ZNF74 as a developmentally expressed gene commonly deleted in DiGeorge syndrome. ZNF74 encodes an RNA-binding protein tightly associated with the nuclear matrix and belongs to a large subfamily of Cys 2 -His 2 zinc finger proteins containing a KRAB (Kruppel-associated box) repressor motif. We now report on the multifunctionality of the zinc finger domain of ZNF74. This nucleic acid binding domain is shown here to function as a nuclear matrix targeting sequence and to be involved in protein-protein interaction. By far-Western analysis and coimmunoprecipitation studies, we demonstrate that ZNF74 interacts, via its zinc finger domain, with the hyperphosphorylated largest subunit of RNA polymerase II (pol IIo) but not with the hypophosphorylated form. The importance of the phosphorylation in this interaction is supported by the observation that phosphatase treatment inhibits ZNF74 binding. Double immunofluorescence experiments indicate that ZNF74 colocalizes with the pol IIo and the SC35 splicing factor in irregularly shaped subnuclear domains. Thus, ZNF74 sublocalization in nuclear domains enriched in pre-mRNA maturating factors, its RNA binding activity, and its direct phosphodependent interaction with the pol IIo, a form of the RNA polymerase functionally associated with premRNA processing, suggest a role for this member of the KRAB multifinger protein family in RNA processing.Zinc finger proteins of the TFIIIA/Kruppel type belong to the largest known family of transcription factors (1, 2). These proteins are characterized by Cys 2 -His 2 zinc finger motifs often repeated in tandem that fold around zinc ions and function as nucleic acid binding domains (3-6). About one-third of mammalian Cys 2 -His 2 zinc finger proteins contain a conserved domain of approximately 75 amino acids called KRAB (Kruppelassociated box) (7). The KRAB domain, located at the N terminus of Cys 2 -His 2 multifinger proteins, can confer strong distance-independent transcriptional repression of both activated and basal RNA polymerase II promoter activity (8 -14). Since they encode a repression motif and a potential DNA binding domain, members from the large KRAB/Cys 2 -His 2 protein family are presently thought to function as transcriptional regulators of gene expression.We previously cloned ZNF74, a gene that encodes a KRAB/ Cys 2 -His 2 protein (15). ZNF74 lies a few kilobases proximal to a polymorphic CA repeat (D22S264) (16) that was shown to be a distal marker for 22q11.2 deletions associated with increased susceptibility to schizophrenia (17). ZNF74 is also one of the few genes found hemizygously deleted in the majority of patients with the DiGeorge syndrome, a microdeletion disorder associated with a wide variety of congenital malformations including cardiac defects, thymic hypoplasia, and hypocalcemia (18 -20). To date, however, both the role of embryologically expressed ZNF74 in the DiGeorge syndrome (19) and its biochemical and cellular functions remain unclear.Although the presence of a KRAB motif and of 1...

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confidence: 61%

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confidence: 88%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Direct Interaction of the KRAB/Cys2-His2Zinc Finger Protein ZNF74 with a Hyperphosphorylated Form of the RNA Polymerase II Largest Subunit

Grondin

Côté

Bazinet

et al. 1997

Journal of Biological Chemistry

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“…The SCAN-box is thought to mediate homo-and hetero-dimerization with other SCAN-containing proteins (Williams et al 1999). While most of these proteins have not been functionally characterized so far, individual members of this group have been reported to have roles in binding and splicing of RNA (Grondin et al 1996), or to repress transcription from RNA polymerase I-, II-and IIIpromoters (reviewed by Urrutia 2003).…”

Section: Discussionmentioning

confidence: 99%

A RAS recruitment screen identifies ZKSCAN4 as a glucocorticoid receptor-interacting protein

Ecker¹,

Lorenz²,

Wolf³

et al. 2008

Journal of Molecular Endocrinology

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To search for proteins interacting with the glucocorticoid receptor, we adapted Aronheim's reverse RAS recruitment system relying on the Saccharomyces cerevisiae mutant cdc25-2, which has a temperature-dependent defect in its RAS signaling pathway driving proliferation. The full-length human glucocorticoid receptor (NR3C1, isoform-a) was attached to the yeast plasma membrane in either of two orientations and used as bait to screen a HeLa cell cDNA library. Library proteins were fused to constitutively active, soluble human RAS, complementing the defective yeast pathway in case of bait-prey interaction. Screening of 800 000 clones resulted in the isolation of 21 proteins, 8 of which were followed up to evaluate interaction with the receptor in human cell lines. One of these candidates, the SCAN-and KRAB-domaincontaining zinc finger protein 307 (ZKSCAN4) was co-precipitated with the receptor when both proteins were overexpressed in HEK293 cells. Rabbit antisera against ZKSCAN4 were raised, affinity purified, and used to immunoprecipitate endogenous ZKSCAN4 from Hct116 cells, resulting in co-precipitation of endogenous glucocorticoid receptor. Overexpressed ZKSCAN4 was found to co-localize in granular nuclear structures with the activated glucocorticoid receptor and partially with chromatin regions characterized by histone H3 mono-methylated on lysine 4 (H3K4me1). Overexpressed ZKSCAN4 had no effect on an episomal glucocorticoid receptor-driven reporter plasmid. By contrast, ZKSCAN4 markedly reduced glucocorticoid induction of the mouse mammary tumor virus-promoter-driven reporter gene when this was chromosomally integrated, arguing for a chromatin-dependent inhibition of glucocorticoid receptor-mediated transactivation.

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NP/NMP4 transcription factors have distinct osteoblast nuclear matrix subdomains

et al. 2000

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The mechanisms underlying the coupling of type I collagen and matrix metalloproteinase (MMP) expression to cell structure and adhesion are poorly understood. We propose that nuclear matrix architectural transcription factors link cell structure and transcription via their association with nuclear matrix subdomains and by their capacity for altering promoter geometry. NP/NMP4 are nuclear matrix proteins that contain from five to eight Cys(2)His(2) zinc fingers. Some NP/NMP4 isoforms bind to the rat type I collagen alpha1(I) polypeptide chain promoter in the manner of architectural transcription factors and alter basal transcription in osteoblast-like cells (Thunyakitpisal et al. in review). Certain isoforms of NP/NMP4 are identical to CIZ, Cas-interacting zinc finger protein, a nucleocytoplasmic shuttling protein that associates with focal adhesions and regulates MMP expression [Nakamoto et al. (2000): Mol Cell Biol 20:1649-1658]. To better understand the role of subnuclear architecture in collagen and MMP expression, we mapped the osteoblast nuclear distribution of NP/NMP4 proteins and identified the functional motifs necessary for nuclear localization and nuclear matrix targeting. Immunofluorescence microscopy was used to determine the cellular and subnuclear distribution of native NP/NMP4 proteins and green fluorescent protein (GFP)-NP/NMP4 fusion proteins in osteoblast-like cells. All GFP-NP/NMP4 fusion proteins localized to the nucleus, but accumulated in distinct nuclear matrix subdomains. The zinc finger domain was necessary and sufficient for nuclear import and matrix targeting. We conclude that the arrangement of the NP/NMP4 zinc fingers largely determines the subnuclear location of these isoforms.

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The KRAB Zinc Finger Gene Encodes an RNA-binding Protein Tightly Associated with the Nuclear Matrix

Cited by 59 publications

References 80 publications

Direct Interaction of the KRAB/Cys2-His2Zinc Finger Protein ZNF74 with a Hyperphosphorylated Form of the RNA Polymerase II Largest Subunit

Direct Interaction of the KRAB/Cys2-His2Zinc Finger Protein ZNF74 with a Hyperphosphorylated Form of the RNA Polymerase II Largest Subunit

A RAS recruitment screen identifies ZKSCAN4 as a glucocorticoid receptor-interacting protein

NP/NMP4 transcription factors have distinct osteoblast nuclear matrix subdomains

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