Cell polarity protein Par3 complexes with DNA-PK via Ku70 and regulates DNA double-strand break repair

Fang, Longhou; Wang, Yiguo; Du, Dan; Yang, Guang; Kwok, Tim Tak; Kong, Siu Kai; Chen, Benjamin; Chen, David J.; Chen, Zhengjun

doi:10.1038/sj.cr.7310145

Cited by 48 publications

(36 citation statements)

References 61 publications

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“…Recently, Fang and colleagues have shown that Par-3 is also present in the nucleus and directly binds to the Ku heterodimer. This interaction is enhanced when cells are exposed to genotoxic stress (g-irradiation or the anticancer agent etoposide phosphate), and knockdown of the protein by RNAi delays the DNA repair response and significantly decreases cell survival in response to ionizing radiation (Fang et al, 2007;Lees-Miller, 2007). These data demonstrate that there is an active crosstalk between the DNA repair machinery and proteins that are traditionally considered to be cytosolic and membrane related, such as Par-3 and small GTPases of the Rho family.…”

Section: Fig 5 Rhoa Activation and Actin Stress Fiber Formation Upomentioning

confidence: 70%

Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival

Guerra

Guidi

Slot

et al. 2011

Journal of Cell Science

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The DNA damage response triggered by bacterial cytolethal distending toxins (CDTs) is associated with activation of the actin-regulating protein RhoA and phosphorylation of the downstream-regulated mitogen-activated protein kinase (MAPK) p38, which promotes the survival of intoxicated (i.e. cells exposed to a bacterial toxin) cells. To identify the effectors of this CDT-induced survival response, we screened a library of 4492 Saccharomyces cerevisiae mutants that carry deletions in nonessential genes for reduced growth following inducible expression of CdtB. We identified 78 genes whose deletion confers hypersensitivity to toxin. Bioinformatics analysis revealed that DNA repair and endocytosis were the two most overrepresented signaling pathways. Among the human orthologs present in our data set, FEN1 and TSG101 regulate DNA repair and endocytosis, respectively, and also share common interacting partners with RhoA. We further demonstrate that FEN1, but not TSG101, regulates cell survival, MAPK p38 phosphorylation, RhoA activation and actin cytoskeleton reorganization in response to DNA damage. Our data reveal a previously unrecognized crosstalk between DNA damage and cytoskeleton dynamics in the regulation of cell survival, and might provide new insights on the role of chronic bacteria infection in carcinogenesis.

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Section: Fig 5 Rhoa Activation and Actin Stress Fiber Formation Upomentioning

confidence: 70%

Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival

Guerra

Guidi

Slot

et al. 2011

Journal of Cell Science

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“…28 We confirmed here, by confocal microscopy, that PAR-3 is expressed by hCMEC/D3 cells and partly localized at cell-cell junctions, together with ZO-1, a prototype TJ-associated protein; a proportion of PAR-3 was also detected in the cytosol and nucleus, in line with previous reports in different cell types. 29,30 We established here, by quantitative confocal microscopy analysis of Podxl and P-gp expression in individual cells, that hCMEC/D3 cells are polarized on Transwell inserts (Figure 2), as previously reported by electron microscopy monitoring of P-gp expression. 23 We further demonstrated that siRNA-mediated PAR-3 knockdown largely prevented the apicobasal-polarized expression of these proteins.…”

Section: Discussionmentioning

confidence: 98%

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Artus

Glacial

Ganeshamoorthy

et al. 2013

J Cereb Blood Flow Metab

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Wnt morphogens released by neural precursor cells were recently reported to control blood-brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/b-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct b-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells. First we established, in the hCMEC/D3 human brain endothelial cell line, that the Par/aPKC PCP complex colocalizes with TJs and controls apicobasal polarization. Second, using an siRNA approach, we showed that the Par/aPKC PCP complex regulates TJ stability and reassembling after osmotic shock. Finally, we provided evidence that Wnt5a signals in hCMEC/D3 cells through activation of the Par/aPKC PCP complex, independently of the Wnt canonical b-catenin-dependent pathway and significantly contributes to TJ integrity and endothelial apicobasal polarity. In conclusion, this study suggests that the Wnt/Par/aPKC PCP pathway, in addition to the Wnt/b-catenin canonical pathway, is a key regulator of the BBB.

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“…For example, apical polarity is present in S1 acini but not in RT4-2 spheroids. Interestingly, PAR3, a tight junction protein involved in apical polarity, was shown to regulate DSB repair by interacting with the Ku70-Ku80 heterodimer (also known as XRCC6-XRCC5) in the nucleus (Fang et al, 2007), and a number of other apical polarity complex proteins can influence chromatin organization (reviewed by Lelièvre, 2010). These observations suggest that both basal and apical poles of the polarity axis influence nuclear functions.…”

Section: Discussionmentioning

confidence: 99%

Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response

Vidi

Chandramouly

Gray

et al. 2012

Journal of Cell Science

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SummaryEpithelial tissue morphogenesis is accompanied by the formation of a polarity axis -a feature of tissue architecture that is initiated by the binding of integrins to the basement membrane. Polarity plays a crucial role in tissue homeostasis, preserving differentiation, cell survival and resistance to chemotherapeutic drugs among others. An important aspect in the maintenance of tissue homeostasis is genome integrity. As normal tissues frequently experience DNA double-strand breaks (DSBs), we asked how tissue architecture might participate in the DNA damage response. Using 3D culture models that mimic mammary glandular morphogenesis and tumor formation, we show that DSB repair activity is higher in basally polarized tissues, regardless of the malignant status of cells, and is controlled by hemidesmosomal integrin signaling. In the absence of glandular morphogenesis, in 2D flat monolayer cultures, basal polarity does not affect DNA repair activity but enhances H2AX phosphorylation, an early chromatin response to DNA damage. The nuclear mitotic apparatus protein 1 (NuMA), which controls breast glandular morphogenesis by acting on the organization of chromatin, displays a polarity-dependent pattern and redistributes in the cell nucleus of basally polarized cells upon the induction of DSBs. This is shown using high-content analysis of nuclear morphometric descriptors. Furthermore, silencing NuMA impairs H2AX phosphorylation -thus, tissue polarity and NuMA cooperate to maintain genome integrity.

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Cell polarity protein Par3 complexes with DNA-PK via Ku70 and regulates DNA double-strand break repair

Cited by 48 publications

References 61 publications

Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival

Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response

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