BACKGROUND: Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the Caenorhabditis elegans
sel-12 presenilin gene cause a highly penetrant egg-laying defect due to reduction of signalling through the
lin-12/Notch receptor. Mutations in six spr genes (for suppressor of presenilin) are known to strongly suppress
sel-12. Mutations in most strong spr genes suppress
sel-12 by de-repressing the transcription of the largely functionally equivalent
hop-1 presenilin gene. However, how mutations in the
spr-2 gene suppress
sel-12 is unknown. RESULTS: We show that
spr-2 mutations increase the levels of
sel-12 transcripts with Premature translation Termination Codons (PTCs) in embryos and L1 larvae. mRNA transcripts from
sel-12 alleles with PTCs undergo degradation by a process known as Nonsense Mediated Decay (NMD). However,
spr-2 mutations do not appear to affect NMD. Mutations in the smg genes, which are required for NMD, can restore
sel-12(PTC) transcript levels and ameliorate the phenotype of
sel-12 mutants with amber PTCs. However, the phenotypic suppression of
sel-12 by smg genes is nowhere near as strong as the effect of previously characterized spr mutations including
spr-2. Consistent with this, we have identified only two mutations in smg genes among the more than 100 spr mutations recovered in genetic screens. CONCLUSION:
spr-2 mutations do not suppress
sel-12 by affecting NMD of
sel-12(PTC) transcripts and appear to have a novel mechanism of suppression. The fact that mutations in smg genes can ameliorate the phenotype of
sel-12 alleles with amber PTCs suggests that some read-through of
sel-12(amber) alleles occurs in smg backgrounds.