Artificial Gene Defect Reveals Target to Fight Genetic Disease

This is immunofluorescence staining of HAP1 cells lacking FANCC gene, treated for 24h with MMC, stained for BRCA1, 53BP1 and DAPI. (Credit: Lydia Robinson Garcia/ CeMM)

DNA repair is essential for a healthy organism. In every day of our lives, tens of thousands of damages occur in the genetic material of our cells. How important those repair mechanisms are, becomes obvious when they fail. 

Fanconi Anaemia (FA) is caused by defective genes for DNA-repair leading to bone marrow failure, developmental abnormalities, and increased cancer risk. 

This is something Joanna Loizou and her research group are focusing on at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. And finding new molecular targets to fight Fanconi anaemia is one of their goals.

In their latest study, published in Nature Communications, the researchers aimed to find additional genes that genetically interact with the diseased FA genes and are essential for the manifestation of the disease, and thereby, if destroyed, restore the ability of the cell to repair DNA crosslinks. 

The research team deployed a novel genetic screen to search for synthetic viable interactions, using a genome-wide loss-of-function approach that uses insertional mutagenesis achieved via a gene-trap approach, on special lines of FA-detective cells that only possess one copy of each gene. 

With this method, they scored a bull’s eye: the researchers found an enzyme that removes ubiquitin, an important regulator of protein activity and half live, to be synthetically viable for FA gene deficiencies. 

When the enzyme, called USP48, was artificially destroyed by CRISPR/Cas9, the FA-deficient cells were less sensitive to DNA-damaging compounds and showed an increased clearance of DNA damage. 

With further molecular analysis of the underlying processes, the researchers were able to show that the inactivation of USP48 in FA-deficient cells even restored a nearly error-free repair of the damaged DNA. 

“Our results show that USP48 inactivation reduces chromosomal instability of DA-defective cells,” principal investigator, Joanna Loizou explained. “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 FA patients.” 


Materials provided by CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Note: Content may be edited for style and length.