PhD

Abstract of my PhD thesis

Structural study of the assembly of human TRF2/RAP1 telomeric complex

  • Prepared under the supervision of Dr Marie-Hélène Le Du in the team “Nuclear envelope, telomeres and DNA repair” of the Department of Biochemistry, Biophysics and Structural Biology (B3S) of the Institute of Integrative Biology of the Cell (I2BC), UMR 9198 CNRS, CEA, Université Paris-Sud.
  • Publicly defended on September 22nd 2015 at the Institut National des Sciences et Techniques du Nucléaire (INSTN), Saclay, France.
  • Thesis prize awarded by the French Crystallographic Association in 2016.

Abstract

Telomeres are the ends of eukaryotic linear chromosomes. They are made of tandem repeats of a short guanine-rich motif and bound by specific proteins. In vertebrates, these proteins form a complex called shelterin, the integrity of which is critical to ensure proper replication of chromosome ends and to protect them against illicit targeting by DNA double-strand break repair pathways. Telomere dysfunctions lead to genome instability, which can ultimately cause senescence or cancer. Telomeres are a subnuclear region in which shelterin proteins are highly enriched, enhancing low affinity interactions of important biological function. Among shelterin proteins, telomeric repeat-binding protein TRF2 and its constitutive partner RAP1 are the main factors responsible for end protection. We studied in details the assembly of TRF2/RAP1 complex by means of integrated structural, biophysical and biochemical approaches. We showed that this assembly displays important conformational adjustments of both proteins, and involves a low affinity interaction engaging large regions in both proteins which affects their interaction properties.

Keywords: telomeres, TRF2, RAP1, SAXS, ITC, crystallography, protein footprinting.

Full text

Because the thesis was defended in a French university and I am a native French speaker, university rules requested it be written in French.

The final version of the manuscript is published in the Thèses en ligne public archive. All source files and full modification history are available as a public git repository.