The genome is full of sequence repetitions. Sequence motif is added after sequence motif, sometimes more than a hundred times. Erratically it seems. And these sequence motifs bind proteins that control transcription factors in regions of the genome where no transcription should occur. A conundrum.
Nicolas Thoma, group leader at the Friedrich Miescher Institute for Biomedical Research, and his team together with the team of David Shore at the University of Geneva, have now been able to give an answer and assign a function to this seeming inconsistency. In a study published in Cell, they elucidated how sequence repeats in telomeres help stabilize these regions and prevent cell death.
Telomeres are at the ends of chromosomes and are composed of DNA repeats. With each cell division, because of the nature of DNA replication, one strand of the DNA becomes shorter and would hence trigger processes leading to cell cycle arrest and eventually cell death. There are a variety of processes in place to ensure that both DNA strands are maintained and that the loss of telomeric sequences through unwanted degradation is minimal. One strategy that has been known for a while is the protective capping of the telomeric ends using a set of dedicated proteins.
Thomä and his colleagues have now dissected the molecular, biochemical and functional properties of this protein cap called the “telosome”. They show by X-ray structural analysis that the common transcription factor Rap1, which binds to the telomere repeats, interacts with two proteins called Rif1 and Rif2 to form a higher-order structure that protects the telomeres. In a VELCRO-like manner, up to 20 Rap1 molecules sitting in an array on the DNA repeats are tightly linked to each other through the Rif proteins. Only once this higher-order structure is in place are chromosomal ends protected from degradation thus allowing the cell to sidestep death.
“In this study we have been able to shed light on the role of sequence repetitions in telomere stability and how a general transcription factor forms the basis for a functionally very powerful protein scaffold that controls telomere homeostasis,” said Thomä. “This is a novel concept and could explain how other regions of the genome with sequence repetitions function to control transcription and cell fate.”
Nicolas Thomä is a group leader at the FMI. He is interested in the machinery that controls the integrity of the DNA. He combines X-ray crystallography with biochemical and biophysical studies to better understand large protein complexes involved in crucial cellular functions such as DNA repair, telomere maintenance and epigenetics in health and disease.
Université de Genève