Understanding regulation mechanisms involving G-quadruplexes by crystallisation of a complex between a G-quadruplex and a protein.

G-quadruplexes (G4s) are nucleic acid structures formed by the stacking of
two or more planes constituted by four guanines each (G-quartets) and
stabilised by cations. Since the visualisation of G4s in vivo, the evidences
that G4 are involved in
various biological processes (ranging from regulating transcription to
modulating alternative splicing and translation) have been reinforced. The
key role of G4s in many diseases (cancers, neurodegenerative diseases,
etc.) is likely connected with
these regulations. Proteins interacting with G4s have been increasingly
identified and this strongly suggests that interactions between G4s and
proteins are important in biological regulations and probably in G4-related
diseases.
The TP53 gene is among the most mutated genes in cancer. It encodes the
p53 protein, a multifunctional tumor suppressor maintaining cellular and
genomic integrity through transcriptional regulation of processes. In various
cellular contexts, the loss of the normal p53 function is both, a prerequisite
for, and a path leading to, tumor outgrowth. p53 has been shown to interact
with G4s from the c-myc and hTERT promoters and with human telomeric
DNA.
Molecular and atomic scale understanding of biological mechanisms and of
their dysregulation or malfunction in diseases are essential for the
development of specific treatments. G4-protein interactions are sparsely
explored but very likely to
constitute a yet-to-be-understood regulation level of the G4-related
biological processes: transcription, splicing, translation, etc.
The present project will contribute to the molecular understanding of the G4-
protein mediated regulations in humans through the characterization of the
interaction between a protein, p53, and a G4 formed by the human
telomeric DNA by determination of an atomic scale structure. This
breakthrough will open up a new research area, improve our understanding
of G4-related diseases and provide new pharmaceutical targets.