20 June 2018

Scientists have discovered that inactivation of a specific enzyme benefits chromosomal instability in cells affected by Fanconi anaemia.

The enzyme may therefore be a potential target for treatment of Fanconi anaemia symptoms, according to Dr Joanna Loizou of the Austrian Academy of Sciences, Vienna, Austria.

Fanconi anaemia creates a problem with DNA repair, which triggers symptoms including bone marrow failure and cancer.

The researchers searched for new molecular targets to fight Fanconi anaemia, by looking for genes that interact with and support the Fanconi anaemia genes and maintain the disease.

The study was published in Nature Communications. The team used a genetic screening method to search for interactions on lines of Fanconi anaemia-defective cells with just one copy of each gene.

This led to the discovery of an enzyme called USP48, which affects protein activity. This enzyme caused Fanconi anaemia-deficient cells to be less sensitive to DNA-damaging compounds when it was artificially destroyed with the gene editing method CRISPR/Cas9.

Dr Loizou and her team report that the Fanconi anaemia-deficient cells were less sensitive to DNA-damaging compounds and showed an increased clearance of DNA damage.

"Our results show that USP48 inactivation reduces chromosomal instability of Fanconi anaemia-defective cells", Dr Loizou explains. "This highlights a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for Fanconi anaemia.

 "To develop USP48 inhibitory molecules could be a new potential approach to alleviate the symptoms of Fanconi anaemia patients".

Source: Velimezi, G., Robinson-Garcia, L., Muñoz-Martínez, F., Wiegant, W.W., da Silva, J.F., Owusu, M., Moder, M., Wiedner, M., Rosenthal, S.B., Fisch, K.M. and Moffat, J., 2018. Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48. Nature Communications, 9(1), p.2280

Link: https://www.nature.com/articles/s41467-018-04649-z

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