4.8 Article

Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein

Journal

NUCLEIC ACIDS RESEARCH
Volume 47, Issue 18, Pages 9950-9966

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz727

Keywords

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Funding

  1. Italian Association for Cancer Research [16730, 18695, 21579]
  2. Regione Campania-POR Campania FESR 2014/2020 [B61G18000470007]
  3. Department of Pharmacy, University of Naples Federico II

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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.

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