Biomedical subjects

Tomas Simonsson

Publications and source records attributed to Tomas Simonsson.

4 recordsLinked to original sources

PubMed2005

Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo.

Telomere end-binding proteins (TEBPs) bind to the guanine-rich overhang (G-overhang) of telomeres. Although the DNA binding properties of TEBPs have been investigated in vitro, little is known about their functions in vivo. Here we use RNA interference to explore in vivo functions of two ciliate TEBPs, TEBPalpha and TEBPbeta. Silencing the expression of genes encoding both TEBPs shows that they cooperate to control the formation of an antiparallel guanine quadruplex (G-quadruplex) DNA structure at telomeres in vivo. This function seems to depend on the role of TEBPalpha in attaching telomeres in the nucleus and in recruiting TEBPbeta to these sites. In vitro DNA binding and footprinting studies confirm the in vivo observations and highlight the role of the C terminus of TEBPbeta in G-quadruplex formation. We have also found that G-quadruplex formation in vivo is regulated by the cell cycle-dependent phosphorylation of TEBPbeta.

Animals↗

PubMed2003

A substrate for telomerase.

Recent data indicates that controlled in vivo synthesis of telomeric DNA is a 'ménage à trois', in which sister chromatid termini paired by telomere end-binding protein constitute a core substrate for a telomerase dimer. Such an arrangement could serve to fine tune synthesis of telomeric DNA and might ensure similar telomerase processivity for paired sister chromatid termini, possibly to secure the maintenance of individual telomere lengths in daughter cells. It also suggests that the bona fide end-capping protein, which is likely to regulate telomerase by restricting access to chromosome termini, has escaped detection in man.

Amino Acid Sequence↗

PubMed2002

c-myc Suppression in Burkitt's lymphoma cells.

The purpose of the study was to elucidate how DNA tetraplex (also referred to as G-quadruplex)-forming oligonucleotides mediate suppression of the human c-myc gene at the level of transcription initiation. A 22-base-long oligonucleotide, which is rich in guanines and folds into an intrastrand DNA tetraplex under physiological conditions, was administered to a Burkitt's lymphoma cell line overexpressing a (8:14) translocated c-myc allele. Administration of the oligonucleotide at nanomolar concentrations to the surrounding medium resulted in efficient cellular uptake, and was accompanied by a substantial concentration- and conformation-dependent decrease in growth rate. We discuss how c-myc transcription is initiated at the molecular level and speculate that the oligonucleotide exerts a dual effect on c-myc expression in vivo.

Alleles↗

PubMed2002

Telomere architecture.

Telomeres are protein-DNA complexes that cap chromosome ends and protect them from being recognized and processed as DNA breaks. Loss of capping function results in genetic instability and loss of cellular viability. The emerging view is that maintenance of an appropriate telomere structure is essential for function. Structural information on telomeric proteins that bind to double and single-stranded telomeric DNA shows that, despite a lack of extensive amino-acid sequence conservation, telomeric DNA recognition occurs via conserved DNA-binding domains. Furthermore, telomeric proteins have multidomain structures and hence are conformationally flexible. A possibility is that telomeric proteins take up different conformations when bound to different partners, providing a simple mechanism for modulating telomere architecture.

Animals↗