title: Two suppressors of sel-12 encode C2H2 zinc-finger proteins that regulate presenilin transcription in Caenorhabditis elegans.
abstract: Mutations in presenilin genes are associated with familial Alzheimer's disease in humans and affect LIN-12/Notch signaling in all organisms tested so far. Loss of sel-12 presenilin activity in Caenorhabditis elegans results in a completely penetrant egg-laying defect. In screens for extragenic suppressors of the sel-12 egg-laying defect, we have isolated mutations in at least five genes. We report the cloning and characterization of spr-3 and spr-4, which encode large basic C(2)H(2) zinc-finger proteins. Suppression of sel-12 by spr-3 and spr-4 requires the activity of the second presenilin gene, hop-1. Mutations in both spr-3 and spr-4 de-repress hop-1 transcription in the early larval stages when hop-1 expression is normally nearly undetectable. As sel-12 and hop-1 are functionally redundant, this suggests that mutations in spr-3 and spr-4 bypass the need for one presenilin by stage-specifically de-repressing the transcription of the other. Both spr-3 and spr-4 code for proteins similar to the human REST/NRSF (Re1 silencing transcription factor/neural-restrictive silencing factor) transcriptional repressors. As other Spr genes encode proteins homologous to components of the CoREST co-repressor complex that interacts with REST, and the INHAT (inhibitor of acetyltransferase) co-repressor complex, our data suggest that all Spr genes may function through the same mechanism that involves transcriptional repression of the hop-1 locus.
authors.affiliation: ABI, Department of Biochemistry, Laboratory of Molecular Neurogenetics, Ludwig-Maximilians-Universitaet, Schillerstr. 44, D-80336 Munich, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lakowski
authors.forename: Stefan
authors.initials: S
authors.lastname: Eimer
authors.forename: Christine
authors.initials: C
authors.lastname: Göbel
authors.forename: Andreas
authors.initials: A
authors.lastname: Böttcher
authors.forename: Babett
authors.initials: B
authors.lastname: Wagler
authors.forename: Ralf
authors.initials: R
authors.lastname: Baumeister
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002107:Caenorhabditis / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005816:Genetic Complementation Test; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016335:Zinc Fingers
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D015801:Helminth Proteins; C109040:Hop-1 protein, C elegans; D008565:Membrane Proteins; D009687:Nuclear Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C095907:SEL-12 protein, C elegans; C474656:SPR-3 protein, C elegans; C474657:SPR-4 protein, C elegans; D014157:Transcription Factors