C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family of Higher Eukaryotic Transcription Factors

Fedotova, Anna; Bonchuk, Artem; Mogila, Vladic; Georgiev, Pavel

doi:10.32607/20758251-2017-9-2-47-58

Cited by 159 publications

(141 citation statements)

References 135 publications

(169 reference statements)

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“…The KRAB domains are widely present in human zinc finger proteins, and considered as potent transcriptional repression modules through interacting with KAP1 and subsequently recruiting histone-modifying proteins (11,33,34). ZNF677, a member of KRAB zinc finger protein family, is only reported to be downregulated by promoter methylation in NSCLC (12).…”

Section: Discussionmentioning

confidence: 99%

“…Zinc finger proteins are the largest transcription factor family in human genome, which have a wide variety of functions in human diseases including cancers through transcriptionally activating or repressing their targets (10). The majority of zinc finger proteins contain Kr€ uppel associated box (KRAB) domains, which has been demonstrated to repress the transcription of their downstream targets (11). As a member of the Kr€ uppel C2H2-type zinc finger protein family, the zinc finger protein 677 (ZNF677) is the least studied, and is only found to be methylated in non-small cell lung cancer (NSCLC; ref.…”

Section: Introductionmentioning

confidence: 99%

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ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer

Yang

Hong-quan

et al. 2018

Cancer Research

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The zinc finger protein 677 (ZNF677) belongs to the zinc finger protein family, which possesses transcription factor activity by binding sequence-specific DNA. Previous studies have reported its downregulated by promoter methylation in non-small cell lung cancer. However, its biological role and exact mechanism in human cancers, including thyroid cancer, remain unknown. In this study, we demonstrate that ZNF677 is frequently downregulated by promoter methylation in primary papillary thyroid cancers (PTC) and show that decreased expression of ZNF677 is significantly associated with poor patient survival. Ectopic expression of ZNF677 in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice and induced cell-cycle arrest and apoptosis. Conversely, knockdown of ZNF677 promoted thyroid cancer cell proliferation and colony formation. ZNF677 exerted its tumor suppressor functions in thyroid cancer cells through transcriptional repression of two targets CDKN3 and HSPB1 (or HSP27), thereby inhibiting phosphorylation and activation of Akt via distinct mechanisms. Taken together, our data show that ZNF677 functions as a tumor suppressor and is frequently silenced via promoter methylation in thyroid cancer. These findings report a tumor suppressive role of the zinc-finger protein ZNF677 in primary papillary thyroid cancer through inhibition of Akt phosphorylation. .

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer

Yang

Hong-quan

et al. 2018

Cancer Research

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“…The ZNF622 protein contains C 2 H 2 zinc finger motifs (Fig. 1B), which are putative DNA-binding modules (57). This prompted us to analyze whether the reintroduced ZNF622(wt)-HA could interact with viral DNA.…”

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confidence: 99%

Cellular Zinc Finger Protein 622 Hinders Human Adenovirus Lytic Growth and Limits Binding of the Viral pVII Protein to Virus DNA

Mun

Punga

2019

J Virol

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Human adenovirus (HAdV) encodes a multifunctional DNA-binding protein pVII, which is involved in virus DNA packaging and extracellular immune signaling regulation. Although the pVII is an essential viral protein, its exact role in the virus life cycle and interplay with cellular proteins have remained to a large extent unclear. We have recently identified the cellular zinc finger protein 622 (ZNF622) as a potential pVII-interacting protein. In this study, we describe the functional consequences of the ZNF622-pVII interplay and the role of ZNF622 in the HAdV life cycle. ZNF622 protein expression increased, and it accumulated similarly to the pVII protein in the nuclei of virus-infected cells. The lack of the ZNF622 protein specifically increased pVII binding to viral DNA in the infected cells and elevated the pVII protein levels in the purified virions. In addition, ZNF622 knockout cells showed an increased cell lysis and enhanced accumulation of the infectious virus particles. Protein interaction studies revealed that ZNF622 forms a trimeric complex with the pVII protein and the cellular histone chaperon protein nucleophosmin 1 (NPM1). The integrity of this complex is important since ZNF622 mutations and NPM1 deficiency changed pVII ability to bind viral DNA. Collectively, our results implicate that ZNF622 may act as a cellular antiviral protein hindering lytic HAdV growth and limiting pVII protein binding to viral DNA.IMPORTANCEHuman adenoviruses (HAdVs) are common human pathogens causing a wide range of acute infections. To counteract viral pathogenicity, cells encode a variety of antiviral proteins and noncoding RNAs to block virus growth. In this study, we show that the cellular zinc finger protein 622 (ZNF622) interacts with an essential HAdV protein known as pVII. This mutual interaction limits pVII binding to viral DNA. Further, ZNF622 has a role in HAdV life cycle since the lack of ZNF622 correlates with increased lysis of the infected cells and accumulation of the infectious virions. Together, our study reveals a novel cellular antiviral protein ZNF622, which may impede lytic HAdV growth.

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“…Finally, we explored the functional significance of the carbonylation of zinc fingers and showed that the ERR family of nuclear receptors are carbonylated in vivo, and this leads to a severe impairment in DNA-binding capacity. Zinc fingers are most commonly observed in DNA-binding proteins and are critical for sequence-specific DNA binding of a wide variety of proteins involved in transcription, replication, and repair (49,50). It is appreciated that these proteins are sensitive to oxidative stress, although the mechanisms by which this occurs remain elusive (34,51).…”

Section: Nuclear Carbonylation Of Zinc Finger Proteinsmentioning

confidence: 99%

Obesity-induced protein carbonylation in murine adipose tissue regulates the DNA-binding domain of nuclear zinc finger proteins

Hauck

Zhou

Hahn

et al. 2018

Journal of Biological Chemistry

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In obesity-linked insulin resistance, oxidative stress in adipocytes leads to lipid peroxidation and subsequent carbonylation of proteins by diffusible lipid electrophiles. Reduction in oxidative stress attenuates protein carbonylation and insulin resistance, suggesting that lipid modification of proteins may play a role in metabolic disease, but the mechanisms remain incompletely understood. Herein, we show that , diet-induced obesity in mice surprisingly results in preferential carbonylation of nuclear proteins by 4-hydroxy--2,3-nonenal (4-HNE) or 4-hydroxy--2,3-hexenal (4-HHE). Proteomic and structural analyses revealed that residues in or around the sites of zinc coordination of zinc finger proteins, such as those containing the C2H2 or MATRIN, RING, C3H1, or N4-type DNA-binding domains, are particularly susceptible to carbonylation by lipid aldehydes. These observations strongly suggest that carbonylation functionally disrupts protein secondary structure supported by metal coordination. Analysis of one such target, the nuclear protein estrogen-related receptor γ (ERR-γ), showed that ERR-γ is modified by 4-HHE in the obese state. carbonylation decreased the DNA-binding capacity of ERR-γ and correlated with the obesity-linked down-regulation of many key genes promoting mitochondrial bioenergetics. Taken together, these findings reveal a novel mechanistic connection between oxidative stress and metabolic dysfunction arising from carbonylation of nuclear zinc finger proteins, such as the transcriptional regulator ERR-γ.

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C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family of Higher Eukaryotic Transcription Factors

Cited by 159 publications

References 135 publications

ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer

ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer

Cellular Zinc Finger Protein 622 Hinders Human Adenovirus Lytic Growth and Limits Binding of the Viral pVII Protein to Virus DNA

Obesity-induced protein carbonylation in murine adipose tissue regulates the DNA-binding domain of nuclear zinc finger proteins

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