Biomedical subjects

Victoria V Lunyak

Publications and source records attributed to Victoria V Lunyak.

7 recordsLinked to original sources

PubMed2006

A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription.

Multiple enzymatic activities are required for transcriptional initiation. The enzyme DNA topoisomerase II associates with gene promoter regions and can generate breaks in double-stranded DNA (dsDNA). Therefore, it is of interest to know whether this enzyme is critical for regulated gene activation. We report that the signal-dependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors, including activating protein 1, requires DNA topoisomerase IIbeta-dependent, transient, site-specific dsDNA break formation. Subsequent to the break, poly(adenosine diphosphate-ribose) polymerase-1 enzymatic activity is induced, which is required for a nucleosome-specific histone H1-high-mobility group B exchange event and for local changes of chromatin architecture. Our data mechanistically link DNA topoisomerase IIbeta-dependent dsDNA breaks and the components of the DNA damage and repair machinery in regulated gene transcription.

Cell Line, Tumor↗

PubMed2006

Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response.

A decade of intensive investigation of coactivators and corepressors required for regulated actions of DNA-binding transcription factors has revealed a network of sequentially exchanged cofactor complexes that execute a series of enzymatic modifications required for regulated gene expression. These coregulator complexes possess "sensing" activities required for interpretation of multiple signaling pathways. In this review, we examine recent progress in understanding the functional consequences of "molecular sensor" and "molecular adaptor" actions of corepressor/coactivator complexes in integrating signal-dependent programs of transcriptional responses at the molecular level. This strategy imposes a temporal order for modifying programs of transcriptional regulation in response to the cellular milieu, which is used to mediate developmental/homeostatic and pathological events.

Allosteric Regulation↗

PubMed2005

No rest for REST: REST/NRSF regulation of neurogenesis.

Epigenetic strategies control the orderly acquisition and maintenance of neuronal traits. A complex network of transcriptional repressors and co-repressors mediates gene specificity for these strategies. In this issue of Cell, a study by Ballas and coworkers (Ballas et al., 2005) provides insight into the early lineage commitment events during neurogenesis. This study demonstrates that regulation of the REST/NRSF transcriptional repressor plays a fundamental role in the progression of pluripotent cells to lineage-restricted neural progenitors.

Animals↗

PubMed2004

REST and peace for the neuronal-specific transcriptional program.

Despite a genetic homogeneity, cells in multicellular organisms are structurally and functionally heterogeneous. The diversity of cell phenotypes exists due to differential transcriptional programs precisely regulated by specific nuclear factors and induced upon differentiation. The differences in gene expression programs arise during development and become heritable during cell proliferation. Over the last few years, research has focused on three molecular mechanisms that mediate epigenetic phenomena: DNA methylation, histone modification, and formation of specialized nuclear domains or territories. All of these processes are dynamic and tightly linked to the organism's development. Here we review advances in understanding the significance of epigenetic mechanisms in the establishment and maintenance of the specialized transcriptional program. We project the accumulated knowledge onto the delineation of the molecular mechanisms by which central nervous system-specific genes are expressed in the nervous system and repressed in other tissues.

Animals↗

PubMed2002

Corepressor-dependent silencing of chromosomal regions encoding neuronal genes.

The molecular mechanisms by which central nervous system-specific genes are expressed only in the nervous system and repressed in other tissues remain a central issue in developmental and regulatory biology. Here, we report that the zinc-finger gene-specific repressor element RE-1 silencing transcription factor/neuronal restricted silencing factor (REST/NRSF) can mediate extraneuronal restriction by imposing either active repression via histone deacetylase recruitment or long-term gene silencing using a distinct functional complex. Silencing of neuronal-specific genes requires the recruitment of an associated corepressor, CoREST, that serves as a functional molecular beacon for the recruitment of molecular machinery that imposes silencing across a chromosomal interval, including transcriptional units that do not themselves contain REST/NRSF response elements.

Animals↗

PubMed2002

An induced Ets repressor complex regulates growth arrest during terminal macrophage differentiation.

Defining the molecular mechanisms that coordinately regulate proliferation and differentiation is a central issue in development. Here, we describe a mechanism in which induction of the Ets repressor METS/PE1 links terminal differentiation to cell cycle arrest. Using macrophages as a model, we provide evidence that METS/PE1 blocks Ras-dependent proliferation without inhibiting Ras-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Antiproliferative effects of METS require its interaction with DP103, a DEAD box-containing protein that assembles a novel corepressor complex. Functional interactions between the METS/DP103 complex and E2F/ pRB family proteins are also necessary for inhibition of cellular proliferation, suggesting a combinatorial code that directs permanent cell cycle exit during terminal differentiation.

Animals↗

PubMed2002

Developmental changes in the Sciara II/9A initiation zone for DNA replication.

Developmentally regulated initiation of DNA synthesis was studied in the fly Sciara at locus II/9A. PCR analysis of nascent strands revealed an initiation zone that spans approximately 8 kb in mitotic embryonic cells and endoreplicating salivary glands but contracts to 1.2 to 2.0 kb during DNA amplification of DNA puff II/9A. Thus, the amplification origin occurs within the initiation zone used for normal replication. The initiation zone left-hand border is constant, but the right-hand border changes during development. Also, there is a shift in the preferred site for initiation of DNA synthesis during DNA amplification compared to that in preamplification stages. This is the first demonstration that once an initiation zone is defined in embryos, its borders and preferred replication start sites can change during development. Chromatin immunoprecipitation showed that the RNA polymerase II 140-kDa subunit occupies the promoter of gene II/9-1 during DNA amplification, even though intense transcription will not start until the next developmental stage. RNA polymerase II is adjacent to the right-hand border of the initiation zone at DNA amplification but not at preamplification, suggesting that it may influence the position of this border. These findings support a relationship between the transcriptional machinery and establishment of the replication initiation zone.

Animals↗