In screens for suppressors of the egg-laying defect of mutations in the C. elegans
sel-12 presenilin gene, several suppressor of presenilin (spr) genes have been identified. Most spr genes encode components of a CoREST-like complex and mutations in these genes suppress
sel-12 by de-repressing the transcription of a second presenilin gene,
hop-1. However, how the gene
spr-2, which encodes a Nucleosome Assembly Protein (NAP) orthologous to the human SET/TAF1Beta oncogene, suppresses
sel-12 has remained unclear. To determine if
spr-2 works through the same mechanism as the other spr genes we examined the transcript levels of the different presenilin genes in
spr-2 mutants. To our surprise,
spr-2 mutations do not de-repress the transcription of
hop-1. Furthermore
spr-2 mutations do not strongly affect the modification of histones around the
hop-1locus. However,
spr-2 mutations appear to reduce Nonsense Mediated Decay (NMD) of
sel-12 transcripts containing early stop mutations, at least in the early larval stages. To determine if defects in NMD can suppress
sel-12 we constructed double mutant strains between
sel-12 and alleles of smg genes. The smg genes are absolutely required for NMD and all alleles tested can restore
sel-12 transcript levels and partially suppress the egg-laying defect of
sel-12 . This indicates that the proteins encoded by the three non-sense
sel-12 alleles tested,
by125,
ty11 and
ar171, retain some residual
sel-12 activity. However, smg mutations do not suppress
sel-12 nearly as well as
spr-2 indicating that
spr-2 suppresses
sel-12 through another mechanism. In the process of this work we realized that a new spr gene we were pursuing,
spr-8, mapped close to the gene
smg-6.
spr-8 has a weak suppressor phenotype and fails to complement
smg-6 for
sel-12 suppression.
spr-8 can suppress the smg-suppressible mutation
unc-54(
r296) and
spr-8(
pf52)contains a mutation in
smg-6. We are presently testing whether smg genes can also suppress the phenotype of a deletion and a missense mutation of
sel-12 and whether any additional smg mutation uncovered in our screen are smg alleles.