PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 9519296

Origin DNA-binding proteins.

A M Edwards·A Bochkarev·L Frappier
View original source ↗Export metadata ↓

Abstract

The first step in DNA replication involves the recognition of origin DNA sequences by origin-binding proteins. The three-dimensional structures of three different origin DNA-binding proteins have recently been solved. These proteins form a structural class distinct from other DNA-binding proteins. One of the origin-binding proteins, Epstein-Barr virus nuclear antigen 1, most likely has two modes of DNA binding; the sequential use of these modes may be important for the initiation of DNA replication.

Explore related subjects

Antigens, Polyomavirus TransformingDNA ReplicationDNA, ViralDNA-Binding ProteinsDimerizationEpstein-Barr Virus Nuclear AntigensHerpesvirus 4, HumanModels, MolecularProtein ConformationReplication OriginSequence HomologyViral ProteinsJournal ArticleReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

A M Edwards, A Bochkarev, L Frappier. 1998. Origin DNA-binding proteins.. https://doi.org/10.1016/s0959-440x(98)80009-2

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed1999

The influence of SV40 immortalization of human fibroblasts on p53-dependent radiation responses.

The simian virus 40 large tumor antigen (SV40 Tag) has been ascribed many functions critical to viral propagation, including binding to the mammalian tumor suppressor p53. Recent studies have demonstrated that SV40-transformed murine cells have functional p53. The status of p53 in SV40-immortalized human cells, however, has not been characterized. We have found that in response to ionizing radiation, p53-dependent p21 transactivation activity is present, albeit reduced, in SV40-immortalized cells and that this activity can be further reduced with either dominant negative p53 expression or higher SV40 Tag expression. Furthermore, overexpression of p53 in SV40-immortalized ataxia-telangiectasia (A-T) cells restores p53-dependent p21 induction to typical A-T levels. All SV40-immortalized cell lines exhibited an absence of G1 arrest. Moreover, all SV40-immortalized cell lines exhibited increased apoptosis relative to primary cells in response to ionizing radiation, suggesting that SV40 immortalization results in a unique phenotype with regard to DNA damage responses.

Antigens, Polyomavirus Transforming↗
PubMed1999

Human neurotropic JC virus early protein deregulates glial cell cycle pathway and impairs cell differentiation.

Progressive multifocal leukoencephalopathy (PML), a human demyelinating disease of the central nervous system (CNS), is induced upon replication of the human neurotropic virus, JCV, in glial cells. Similar to other polyomaviruses, replication of JCV is initiated and orchestrated by the viral early protein, T-antigen, and results in the cytolytic destruction of oligodendrocytes, the subset of glial cells responsible for myelin production, and the appearance of bizarre astrocytic glial cells in affected individuals. Earlier results from studies in transgenic animals have suggested that in the absence of viral replication, expression of JCV T-antigen induces pathology consistent with hypomyelination of the brain. These observations suggest that JCV T-antigen has the ability to deregulate oligodendrocyte and perhaps astrocyte function in the CNS. Here we demonstrate that expression of JCV T-antigen in the bipotential glial cell line, CG-4, severely affects the ability of these cells to differentiate toward oligodendrocyte and astrocyte lineages as evidenced by their distinct morphological changes. Examination of the activity of cell cycle regulatory proteins including cyclins and their associated kinases reveals that in the absence of T-antigen, differentiation of CG-4 cells toward astrocytes and oligodendrocytes is accompanied by a decline in cyclin E, cdk2, cyclin A, and cyclin B activity. In contrast, cdc2 activity increased upon CG-4 differentiation. In T-antigen-producing cells, distinct variations in the activity of several cyclins was observed. For example, while the activity of cdk2 and cyclin E was enhanced in T-antigen expressing astrocytes compared to their levels in control cells, the activity of cdc2 was decreased in this cell type. In oligodendrocytes, expression of T-antigen decreased the activity of several cyclins and cdks including cyclin E and cdc2. On the other hand, the level of expression and activity of cyclin A was increased. Thus, it is evident that JCV T-antigen deregulates several important cell cycle regulators during CG-4 differentiation, and these alterations may contribute to the process of cell growth and differentiation in glial cells. The importance of our findings with regard to the neuropathogenesis of PML is discussed.

Antigens, Polyomavirus Transforming↗
PubMed1999

Retinoic acid inhibits transformation by preventing phosphatidylinositol 3-kinase dependent activation of the c-fos promoter.

Retinoic acid inhibits transformation of cells by polyoma virus middle T oncoprotein. Inhibition of transformation results from a retinoic acid-dependent failure of cells to fully express the c-fos proto-oncogene. Retinoic acid prevents transactivation of the c-fos promoter by disrupting signaling between tyrosine kinases at the plasma membrane and trans-acting factors at the c-fos promoter. We used complementary genetic, biochemical and molecular approaches to demonstrate that: (1) phosphatidylinositol 3-kinase signaling is the principle mechanism of polyoma virus middle T oncoprotein activation of c-fos expression; (2) middle T/phosphatidylinositol 3-kinase transactivation of the c-fos promoter and transformation of cells requires activation of both the small GTP-binding protein Rac and Jun N-terminal kinase; (3) retinoic acid inhibits activation of Jun N-terminal kinase, thereby preventing c-fos transactivation and transformation; and (4) middle T activation of c-fos transcription requires both the serum response element and the promoter proximal cyclic AMP response element. These studies identify a novel target through which retinoids prevent oncogenic transformation.

Antigens, Polyomavirus Transforming↗