Active regions of the genome are particularly fragile and DNA double-strand breaks can occur in genes that are being transcribed. Particular RNA/DNA hybrid structures, also called "R-loops", tend to accumulate at these breaks in active genes.
In a paper published in Nature Communications, Gaëlle Legube's team (MCD-CBI) shows that in the absence of dissolution of RNA/DNA hybrids, the BLM (DNA helicase) protein promotes abnormal DNA synthesis at breaks, which leads to cell toxicity. These results provide insight into the mechanism by which the accumulation of R-loops at DNA breaks is toxic.
© Ikrame Lazar, Nadine Puget et Gaëlle Legube
© Ikrame Lazar et Gaëlle Legube
Figure : Model of BLM recruitment following induced DNA double-strand breaks in active genes. In the absence of senataxin (SETX), R-loops accumulate and promote the recruitment of BLM which, in a coordinated manner with POLD3, induces improper DNA repair, these mechanisms resulting in high cellular toxicity.
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