Maria Zannis‐Hadjopoulos

McGill University

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Gerald B. Price

Science Research Laboratory

Domenic Di Paola

McGill University

Emmanouil Rampakakis

McGill University

Christopher E. Pearson

University of Toronto

Diamanto Matheos

McGill University

Olivia Novac

McGill University

Marcia T. Ruiz

Pfizer (Canada)

Torsten O. Nielsen

University of British Columbia

DÁ

David Álvarez

Harvard University

Mario Callejo

Université de Montréal

Cooperative Institutions

McGill University

McGill University Health Centre

National Institutes of Health

Harvard University

National Institute of Diabetes and Digestive and Kidney Diseases

Université de Montréal

National and Kapodistrian University of Athens

Centre National de la Recherche Scientifique

Jewish General Hospital

University of Toronto

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Human Cruciform Binding Protein Belongs to the 14-3-3 Family

Biochemistry (1998)

Andrea Todd Nandini Cossons Alastair Aitken Gerald B. Price Maria Zannis‐Hadjopoulos

Cruciform DNA has been implicated in the initiation of DNA replication. Recently, we identified and purified from human (HeLa) cells a protein, CBP, with binding specificity for cruciform DNA. We have reported previously that the CBP activity sediments at approximately 66 kDa in a glycerol gradient. Here, photochemical cross-linking studies and Southwestern analyses confirm that a 70 kDa polypeptide interacts specifically with cruciform DNA. Microsequence analysis of tryptic peptides of the 70 kDa CBP reveals that it is 100% homologous to the 14-3-3 family of proteins and shows that CBP contains the ε, β, γ, and ζ isoforms of the 14-3-3 family. In addition to polypeptides with the characteristic molecular mass of 14-3-3 proteins (30 and 33 kDa), CBP also contains a polypeptide of 35 kDa which is recognized by an antibody specific for the ε isoform of 14-3-3. Cruciform-specific binding activity is also detected in 14-3-3 proteins purified from sheep brain. Immunofluorescene studies confirm the presence of the ε, β, and ζ isoforms of 14-3-3 proteins in the nuclei of HeLa cells. The 14-3-3 family of proteins has been implicated in cell cycle control, and members of this family have been shown to interact with various signaling proteins. Cruciform binding is a new activity associated with the 14-3-3 family.

Cruciform

HeLa

Protein family

10.1021/bi980768k

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Citations (51)

Cloning of nascent monkey DNA synthesized early in the cell cycle.

Molecular and Cellular Biology (1985)

Gabriel Kaufmann Maria Zannis‐Hadjopoulos R G Martin

To study the structure and complexity of animal cell replication origins, we have isolated and cloned nascent DNA from the onset of S phase as follows: African green monkey kidney cells arrested in G1 phase were serum stimulated in the presence of the DNA replication inhibitor aphidicolin. After 18 h, the drug was removed, and DNA synthesis was allowed to proceed in vivo for 1 min. Nuclei were then prepared, and DNA synthesis was briefly continued in the presence of Hg-dCTP. The mercury-labeled nascent DNA was purified in double-stranded form by extrusion (M. Zannis-Hadjopoulos, M. Perisco, and R. G. Martin, Cell 27:155-163, 1981) followed by sulfhydryl-agarose affinity chromatography. Purified nascent DNA (ca. 500 to 2,000 base pairs) was treated with mung bean nuclease to remove single-stranded ends and inserted into the NruI site of plasmid pBR322. The cloned fragments were examined for their time of replication by hybridization to cellular DNA fractions synthesized at various intervals of the S phase. Among five clones examined, four hybridized preferentially with early replicating fractions.

Aphidicolin

Nuclease

10.1128/mcb.5.4.721

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Citations (47)

Ku Protein Levels, Localization and Association to Replication Origins in Different Stages of Breast Tumor Progression

Journal of Cancer (2013)

Khalil Abdelbaqi Domenic Di Paola Emmanouil Rampakakis Maria Zannis‐Hadjopoulos

Human origins of DNA replication are specific sequences within the genome whereby DNA replication is initiated. A select group of proteins, known as the pre-replication (pre-RC) complex, in whose formation the Ku protein (Ku70/Ku86) was shown to play a role, bind to replication origins to initiate DNA replication. In this study, we have examined the involvement of Ku in breast tumorigenesis and tumor progression and found that the Ku protein expression levels in human breast metastatic (MCF10AC1a) cells were higher in the chromatin fraction compared to hyperplastic (MCF10AT) and normal (MCF10A) human breast cells, but remained constant in both the nuclear and cytoplasmic fractions. In contrast, in human intestinal cells, the Ku expression level was relatively constant for all cell fractions. Nascent DNA abundance and chromatin association of Ku70/86 revealed that the c-myc origin activity in MCF10AC1a is 2.5 to 5-fold higher than in MCF10AT and MCF10A, respectively, and Ku was bound to the c-myc origin more abundantly in MCF10AC1a, by approximately 1.5 to 4.2-fold higher than in MCF10AT and MCF10A, respectively. In contrast, similar nascent DNA abundance and chromatin association was found for all cell lines for the lamin B2 origin, associated with the constitutively active housekeeping lamin B2 gene. Electrophoretic mobility shift assays (EMSAs) performed on the nuclear extracts (NEs) of the three cell types revealed the presence of protein-DNA replication complexes on both the c-myc and lamin B2 origins, but an increase in binding activity was observed from normal, to transformed, to cancer cells for the c-myc origin, whereas no such difference was seen for the lamin B2 origin. Overall, the results suggest that increased Ku chromatin association, beyond wild type levels, alters cellular processes, which have been implicated in tumorigenesis.

Ku70

Replication timing

Origin recognition complex

High-mobility group

Nuclear lamina

Pre-replication complex

10.7150/jca.6289

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Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins

The Journal of Cell Biology (2011)

Maria Sideridou Roubini Zakopoulou Konstantinos Evangelou Michalis Liontos Athanassios Kotsinas

E-cadherin (CDH1) loss occurs frequently in carcinogenesis, contributing to invasion and metastasis. We observed that mouse and human epithelial cell lines overexpressing the replication licensing factor Cdc6 underwent phenotypic changes with mesenchymal features and loss of E-cadherin. Analysis in various types of human cancer revealed a strong correlation between increased Cdc6 expression and reduced E-cadherin levels. Prompted by these findings, we discovered that Cdc6 repressed CDH1 transcription by binding to the E-boxes of its promoter, leading to dissociation of the chromosomal insulator CTCF, displacement of the histone variant H2A.Z, and promoter heterochromatinization. Mutational analysis identified the Walker B motif and C-terminal region of Cdc6 as essential for CDH1 transcriptional suppression. Strikingly, CTCF displacement resulted in activation of adjacent origins of replication. These data demonstrate that Cdc6 acts as a molecular switch at the E-cadherin locus, linking transcriptional repression to activation of replication, and provide a telling example of how replication licensing factors could usurp alternative programs to fulfill distinct cellular functions.

CTCF

Replication timing

10.1083/jcb.201108121

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Citations (91)

Comparative analysis of pre‐replication complex proteins in transformed and normal cells

Journal of Cellular Biochemistry (2011)

Domenic Di Paola Maria Zannis‐Hadjopoulos

This study examines the abundance of the major protein constituents of the pre-replication complex (pre-RC), both genome-wide and in association with specific replication origins, namely the lamin B2, c-myc, 20mer1, and 20mer2 origins. Several pre-RC protein components, namely ORC1-6, Cdc6, Cdt1, MCM4, MCM7, as well as additional replication proteins, such as Ku70/86, 14-3-3, Cdc45, and PCNA, were comparatively and quantitatively analyzed in both transformed and normal cells. The results show that these proteins are overexpressed and more abundantly bound to chromatin in the transformed compared to normal cells. Interestingly, the 20mer1, 20mer2, and c-myc origins exhibited a two- to threefold greater origin activity and a two- to threefold greater in vivo association of the pre-RC proteins with these origins in the transformed cells, whereas the origin associated with the housekeeping lamin B2 gene exhibited both similar levels of activity and in vivo association of these pre-RC proteins in both cell types. Overall, the results indicate that cellular transformation is associated with an overexpression and increased chromatin association of the pre-RC proteins. This study is significant, because it represents the most systematic comprehensive analysis done to date, using multiple replication proteins and different replication origins in both normal and transformed cell lines.

Origin recognition complex

Licensing factor

Replication factor C

Pre-replication complex

10.1002/jcb.24006

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Citations (24)

DNA cruciforms and the nuclear supporting structure

Experimental Cell Research (1991)

G. K. Ward Awatef Shihab-El-Deen Maria Zannis‐Hadjopoulos Gerald B. Price

10.1016/0014-4827(91)90503-m

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Citations (36)

Anti-cruciform Monoclonal Antibody and Cruciform DNA Interaction

Journal of Molecular Biology (1995)

Katrin Steinmetzer Maria Zannis‐Hadjopoulos Gerald B. Price

Cruciform

Footprinting

DNA footprinting

10.1006/jmbi.1995.0596

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Citations (20)

Relationship of Simian Virus 40 Tumor Antigens to Virus-Induced Mutagenesis

Molecular and Cellular Biology (1983)

Maria Zannis‐Hadjopoulos Robert G. Martin

We analyzed the mutation frequency to 8-azaguanine (8AZ) resistance in rat FR3T3 cells acutely infected with simian virus 40 wild type and tsA and early deletion mutants and in a series of temperature-sensitive (N) and temperature-insensitive (A) transformants derived from Chinese hamster lung (CHL) cells. Upon acute infection, the frequency of mutation to 8AZ resistance was raised at most by two- to eightfold over the spontaneous frequency, and it was independent of the presence of a functional 90,000-molecular-weight T antigen or 20,000-molecular-weight t antigen or both. Similarly, in the stable transformants of CHL cells, no correlation was found between functional T antigens and mutation to 8AZ resistance. It therefore seems unlikely that simian virus 40-induced transformation results from any mutagenic activity of this virus.

Simian

Chinese hamster

Mutation frequency

10.1128/mcb.3.3.421-428.1983

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Citations (5)

Eucaryotic replication origin binding proteins

Frontiers in bioscience (2004)

Maria Zannis‐Hadjopoulos

Initiation of eukaryotic DNA replication is a tightly controlled process. Replication initiates at multiple specific sites (replication origins) that have been licensed for replication, following the cell cycle-dependent, multi-step assembly of specific factors. Thus, replication origins occur in two chromatin states: a replication-competent pre-replicative (pre-RC) state, when a number of replication proteins assemble on the origin in a stepwise fashion, and a replication-incompetent post-replicative (post-RC) state, in which the origin (or elements of it) is bound only by the origin recognition complex (ORC) (or subunits of it). This review summarizes the origin binding proteins that have been have been identified to date.

Origin recognition complex

Pre-replication complex

Licensing factor

Replication factor C

Replication

Minichromosome maintenance

10.2741/1369

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Citations (21)

In vivo association of 14-3-3 isoforms with mammalian origins of DNA replication

Biochemical Society Transactions (2002)

Olivia Novac David Álvarez Gerald B. Price Maria Zannis‐Hadjopoulos

Conference Abstract| June 01 2002 In vivo association of 14-3-3 isoforms with mammalian origins of DNA replication O. Novac; O. Novac 1McGill University, 3655 promenade sir william osler, Montreal, Quebec, Canada, H3G 1Y6 Search for other works by this author on: This Site PubMed Google Scholar D. Alvarez; D. Alvarez 1McGill University, 3655 promenade sir william osler, Montreal, Quebec, Canada, H3G 1Y6 Search for other works by this author on: This Site PubMed Google Scholar G. B. Price; G. B. Price 1McGill University, 3655 promenade sir william osler, Montreal, Quebec, Canada, H3G 1Y6 Search for other works by this author on: This Site PubMed Google Scholar M. Zannis-Hadjopoulos M. Zannis-Hadjopoulos 1McGill University, 3655 promenade sir william osler, Montreal, Quebec, Canada, H3G 1Y6 Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2002) 30 (3): A63. https://doi.org/10.1042/bst030a063c Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation O. Novac, D. Alvarez, G. B. Price, M. Zannis-Hadjopoulos; In vivo association of 14-3-3 isoforms with mammalian origins of DNA replication. Biochem Soc Trans 1 June 2002; 30 (3): A63. doi: https://doi.org/10.1042/bst030a063c Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2002 Biochemical Society2002 Article PDF first page preview Close Modal You do not currently have access to this content.

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Replication

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10.1042/bst030a063c

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