Title
Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein
Author
Jussara Amato, Linda Cerofolini, Diego Brancaccio, Stefano Giuntini, Nunzia Iaccarino, Pasquale Zizza, Sara Iachettini, Annamaria Biroccio, Ettore Novellino, Antonio Rosato, Marco Fragai, Claudio Luchinat, Antonio Randazzo, Bruno Pagano
Year
2019
Journal
Nucleic Acids Research
Abstract
HMGB1 is a ubiquitous non-histone protein, which biological effects depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription and telomere maintenance. HMGB1 has been reported to bind preferentially to bent DNA as well as to noncanonical DNA structures like 4-way junctions and, more recently, to G-quadruplexes. These are four-stranded conformations of nucleic acids involved in important cellular processes, including telomere maintenance. In this frame, G-quadruplex recognition by specific proteins represents a key event to modulate physiological or pathological pathways. Herein, to get insights into the telomeric G-quadruplex DNA recognition by HMGB1, we performed detailed biophysical studies complemented with biological analyses. The obtained results provided information about the molecular determinants for the interaction and showed that the structural variability of human telomeric G-quadruplex DNA may have significant implications in HMGB1 recognition. The biological data identified HMGB1 as a telomere-associated protein in both telomerase-positive and -negative tumor cells and showed that HMGB1 gene silencing in such cells induces telomere DNA damage foci. Altogether, these findings provide a deeper understanding of telomeric G-quadruplex recognition by HMGB1 and suggest that this protein could actually represent a new target for cancer therapy.
Instrument
FP-8300, J-815
Keywords
Circular dichroism, G-quadruplex structure, Chemical stability, Ligand binding, Thermal stability, Fluorescence, Biochemistry