Chromatin remodelling protein ATRX is involved in resolution of G-quadruplexes across the genome — ASN Events
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  3. Chromatin remodelling protein ATRX is involved in resolution of G-quadruplexes across the genome

Chromatin remodelling protein ATRX is involved in resolution of G-quadruplexes across the genome (#283)

Inmaculada Matilla Fernandez 1 , Christine E Napier 1 , Marie-Paule Teulade-Fichou 2 , Hilda A Pickett 1 , Jennifer L Beck 3 , Roger R Reddel 1 , Tracy M Bryan 1
  1. Children's Medical Research Institute, Westmead, NSW, Australia
  2. Institut Curie, Paris, France
  3. University of Wollongong, Wollongong, NSW, Australia

In many cancers, telomeres are lengthened by an homologous recombination (HR)-dependent DNA synthesis mechanism, Alternative Lengthening of Telomeres (ALT). Expression of the chromatin-remodelling protein ATRX is often lost in ALT cancers and cell lines1-3. ATRX has a role in facilitating DNA replication4,5, and has been found to localize to regions of the genome with the potential to form the four-stranded structures known as G-quadruplexes6. Using a G-quadruplex-specific antibody7, we have made the intriguing observation that several small molecules that stabilize G-quadruplexes cause a dramatic increase in occurrence of these structures across the genome of ALT cells, relative to cells using telomerase. The absence of ATRX contributes to this susceptibility to genome-wide G-quadruplex stabilisation, demonstrating that ATRX plays a role in removal of G-quadruplexes from the genome. Consistent with the described propensity of G-quadruplexes to trigger HR and genomic instability8-10, we also find that the telomeric recombination characteristic of ALT is promoted by G-quadruplex ligands; the resulting genome instability may contribute to the demise of the cells. The data support the hypotheses that i) ALT cells are especially susceptible to replication fork stalling due to stabilization of G-quadruplex DNA at their telomeres and elsewhere in the genome, ii) G-quadruplexes are involved in the induction of recombination at ALT telomeres, and iii) the role of ATRX in the facilitation of DNA replication involves an ability to deal with structured DNA such as G-quadruplexes.

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