Dephosphorylation of Barrier-to-autointegration Factor by Protein Phosphatase 4 and Its Role in Cell Mitosis

Zhuang, Xiaolei; Семенова, Е. А.; Maric, Dragan; Craigie, Robert

doi:10.1074/jbc.m113.492777

Cited by 59 publications

(63 citation statements)

References 39 publications

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“…Indeed, when CV1 cells were treated with phosphatase inhibitor, increased accumulation of hyperphosphorylated BAF correlating with increased inhibitor concentration could be observed. While these experiments were ongoing, it was discovered that BAF dephosphorylation can be mediated by two phosphatases, PP2A and PP4 (32,34). In this study, we validated that PP2A is a BAF phosphatase and that upon its depletion, phosphorylated BAF accumulated in our CV1 cells as has been described previously (32).…”

Section: Discussionsupporting

confidence: 85%

“…In support of this model, it has recently been observed that at least two phosphatases, PP2A and PP4, can act on BAF (32,34). Those studies showed that siRNA-mediated depletion of the catalytic subunit of either PP2A or PP4 led to the accumulation of hyperphosphorylated BAF in cell culture and C. elegans (32,34). Therefore, we tested whether BAF phosphatases were capable of modulating BAF phosphorylation, localization, or antipoxviral activity in our cell system.…”

Section: Fig 5 Relocalization Of Baf and Its Mutants To Viral Replicamentioning

confidence: 58%

“…This leads us to posit that WT BAF is dephosphorylated in the cytoplasm to "activate" its antiviral activity. In support of this model, it has recently been observed that at least two phosphatases, PP2A and PP4, can act on BAF (32,34). Those studies showed that siRNA-mediated depletion of the catalytic subunit of either PP2A or PP4 led to the accumulation of hyperphosphorylated BAF in cell culture and C. elegans (32,34).…”

Section: Fig 5 Relocalization Of Baf and Its Mutants To Viral Replicamentioning

confidence: 83%

“…For example, BAF is a substrate of the cellular vaccinia-related kinases (VRKs) (28,(30)(31)(32)(33) and protein phosphatases PP2A and PP4 (32,34). These enzymes are critical regulators of BAF's mitotic function, controlling its interaction with DNA and other proteins (28,31,32,35).…”

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confidence: 99%

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Cell- and Virus-Mediated Regulation of the Barrier-to-Autointegration Factor's Phosphorylation State Controls Its DNA Binding, Dimerization, Subcellular Localization, and Antipoxviral Activity

Jamin

Wicklund

Wiebe

2014

J Virol

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Barrier-to-autointegration factor (BAF) is a DNA binding protein with multiple cellular functions, including the ability to act as a potent defense against vaccinia virus infection. This antiviral function involves BAF's ability to condense double-stranded DNA and subsequently prevent viral DNA replication. In recent years, it has become increasingly evident that dynamic phosphorylation involving the vaccinia virus B1 kinase and cellular enzymes is likely a key regulator of multiple BAF functions; however, the precise mechanisms are poorly understood. Here we analyzed how phosphorylation impacts BAF's DNA binding, subcellular localization, dimerization, and antipoxviral activity through the characterization of BAF phosphomimetic and unphosphorylatable mutants. Our studies demonstrate that increased phosphorylation enhances BAF's mobilization from the nucleus to the cytosol, while dephosphorylation restricts BAF to the nucleus. Phosphorylation also impairs both BAF's dimerization and its DNA binding activity. Furthermore, our studies of BAF's antiviral activity revealed that hyperphosphorylated BAF is unable to suppress viral DNA replication or virus production. Interestingly, the unphosphorylatable BAF mutant, which is capable of binding DNA but localizes predominantly to the nucleus, was also incapable of suppressing viral replication. Thus, both DNA binding and localization are important determinants of BAF's antiviral function. Finally, our examination of how phosphatases are involved in regulating BAF revealed that PP2A dephosphorylates BAF during vaccinia infection, thus counterbalancing the activity of the B1 kinase. Altogether, these data demonstrate that phosphoregulation of BAF by viral and cellular enzymes modulates this protein at multiple molecular levels, thus determining its effectiveness as an antiviral factor and likely other functions as well. IMPORTANCEThe barrier-to-autointegration factor (BAF) contributes to cellular genomic integrity in multiple ways, the best characterized of which are as a host defense against cytoplasmic DNA and as a regulator of mitotic nuclear reassembly. Although dynamic phosphorylation involving both viral and cellular enzymes is likely a key regulator of multiple BAF functions, the precise mechanisms involved are poorly understood. Here we demonstrate that phosphorylation coordinately regulates BAF's DNA binding, subcellular localization, dimerization, and antipoxviral activity. Overall, our findings provide new insights into how phosphoregulation of BAF modulates this protein at multiple levels and governs its effectiveness as an antiviral factor against foreign DNA.

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Section: Discussionsupporting

confidence: 85%

Section: Fig 5 Relocalization Of Baf and Its Mutants To Viral Replicamentioning

confidence: 58%

Section: Fig 5 Relocalization Of Baf and Its Mutants To Viral Replicamentioning

confidence: 83%

mentioning

confidence: 99%

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Cell- and Virus-Mediated Regulation of the Barrier-to-Autointegration Factor's Phosphorylation State Controls Its DNA Binding, Dimerization, Subcellular Localization, and Antipoxviral Activity

Jamin

Wicklund

Wiebe

2014

J Virol

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“…BanF1 localises to the nuclear membrane [206] and is involved in chromatin condensation and nuclear lamina assembly [207,208], cell cycle progression [209]. More recently it has been found to have a direct role in genomic stability, via sister chromatid decatenation following DNA replication [210].…”

Section: (B) Nucleotide Excision Repair (Ner) Pathway and Cisplatin Rmentioning

confidence: 99%

Individualising care of tongue cancer using markers of genomic stability

Jenkins¹

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Treatment outcomes and prognostic accuracy for oral tongue cancer has had little substantial improvement in the last 20 years. Adjuvant therapy toxicity is high, and there are no clinical tests that accurately stratify which high-risk cancers are likely to benefit, and which will recur despite treatment. Genomic instability is an inherent force in all cancer, however there are substantial differences in which defective repair pathways cause malignancy and contribute to invasion and metastasis.Tongue cancer is relatively aetiologically homogenous, as it is associated mostly with tobacco exposure, exhibits early lymphatic invasion, and is sensitive to particular DNA-damaging agents, making it an attractive disease target for investigating the prognostic potential of genomic stability markers. The aim of this study is to evaluate the prognostic and predictive implications of genomic instability in primary oral tongue cancer.Molecular tumour diagnostics is a burgeoning field, complicated by a paucity of wellpowered trials demonstrating clinical outcomes. DNA repair proteins as biomarkers have been mostly studied in genetic assays, from severe repair syndrome phenotypes to BRCA gene inactivation in breast and ovarian cancer. De-novo mutations in repair genes have been less frequently characterized across sporadic or exposure-related cancers. Almost all cancers exhibit mutation of nuclear DNA resulting in deregulation of the cell cycle and repair process. The most deleterious lesion is the double-strand break (DSB), and defects in this repair pathway cause both increased aggressive features (heterogeneity, invasion and metastasis) and sensitivity to chemoradiotherapy. This study will examine eight markers of genomic stability across three principal domains;1. Markers of repair of specific lesions induced by standard chemotherapy for oral tongue cancer (treatment prediction) 2. Markers implicated in genetic susceptibility studies in oral squamous cell cancer (phenotype stratification) 3 3. Markers of the DNA damage response and DSB repair (genomic stability)A key study strategy is the creation and utilisation of a tissue microarray resource to economically assess the relatively large number of markers in the context of limited source tissue. A microarray of fifty-five (55) included patients was constructed from stored surgical specimen blocks. Immunohistochemical stains were performed, and grading scales constructed under the guidance of a clinical pathologist (Dr Duncan Lambie).The hypothesis of this study is that genomic instability of primary tumours is a characteristic that is important for both prognosis and treatment prediction, and that this can be quantified using immunohistochemical methods. We have identified two important patient subgroups that show significant prognostic differentiation in our markers and discuss the implications for clinical management. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The Univ...

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The role of inner nuclear membrane proteins in tumourigenesis and as potential targets for cancer therapy

Rose

Burgess

O’Byrne

et al. 2022

Cancer Metastasis Rev

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Despite significant advances in our understanding of tumourigenesis and cancer therapeutics, cancer continues to account for 30% of worldwide deaths. Therefore, there remains an unmet need for the development of cancer therapies to improve patient quality of life and survival outcomes. The inner nuclear membrane has an essential role in cell division, cell signalling, transcription, cell cycle progression, chromosome tethering, cell migration and mitosis. Furthermore, expression of several inner nuclear membrane proteins has been shown to be frequently altered in tumour cells, resulting in the dysregulation of cellular pathways to promote tumourigenesis. However, to date, minimal research has been conducted to investigate how targeting these dysregulated and variably expressed proteins may provide a novel avenue for cancer therapies. In this review, we present an overview of the involvement of the inner nuclear membrane proteins within the hallmarks of cancer and how they may be exploited as potent anti-cancer therapeutics.

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Dephosphorylation of Barrier-to-autointegration Factor by Protein Phosphatase 4 and Its Role in Cell Mitosis

Cited by 59 publications

References 39 publications

Cell- and Virus-Mediated Regulation of the Barrier-to-Autointegration Factor's Phosphorylation State Controls Its DNA Binding, Dimerization, Subcellular Localization, and Antipoxviral Activity

Cell- and Virus-Mediated Regulation of the Barrier-to-Autointegration Factor's Phosphorylation State Controls Its DNA Binding, Dimerization, Subcellular Localization, and Antipoxviral Activity

Individualising care of tongue cancer using markers of genomic stability

The role of inner nuclear membrane proteins in tumourigenesis and as potential targets for cancer therapy

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