The synthetic lethality relationship appears when the product of gene X is rendered non-functional by the action of the drug.
Elevated levels of BPIF proteins in CF, in the face of chronic infection and inflammation, suggest that the protein is rendered non-functional by the abnormal milieu present in the airways of CF patients.
Firstly, the tyrosine phosphorylation of Gab1 is drastically reduced in mouse embryonic fibroblasts (MEFs) lacking Grb2 or expressing a functionally impaired Grb2 protein in which its SH2 domain has been rendered non-functional by the E89K knock-in mutation [ 60].
To test these particular structural variants in model animals, accurate genome editing is required to produce equivalent mutations to human variants rather than producing only simple KO models where entire coding genes are rendered non-functional.
Most loci are rendered non-functional by mutations, but several intact retroviral genes are known in mammalian genomes.
Following either tandem or segmental duplication events, one of the duplicated genes can be rendered non-functional via the accumulation of deleterious mutations [6].
On the other hand, only a limited number of LINEs and LTR elements are full-length; many of which are rendered non-functional due to point mutations and deletions [4].
FtsK subunits were rendered non-functional by mutation in the highly conserved ATP-binding pocket.
Therefore it seems well conceivable that many genes, including SLC1A8 and SLC1A9, may have been rendered non-functional during these rearrangement events.
Nevertheless, it is still not clear whether the mechanisms by which these genes are rendered non-functional might be relevant to the natural history of the tumours and to the changes that arise and are selected throughout the oncogenic process.
Even if it could not be excluded that the coding sequence could also contain miRNA target sequences that are functional in translation regulation, they would most likely be rendered non-functional by traversing ribosomes during translation.
