title: Mpn1, mutated in poikiloderma with neutropenia protein 1, is a conserved 3'-to-5' RNA exonuclease processing U6 small nuclear RNA.
abstract: Clericuzio-type poikiloderma with neutropenia (PN) is a rare genodermatosis associated with mutations in the C16orf57 gene, which codes for the uncharacterized protein hMpn1. We show here that, in both fission yeasts and humans, Mpn1 processes the spliceosomal U6 small nuclear RNA (snRNA) posttranscriptionally. In Mpn1-deficient cells, U6 molecules carry 3' end polyuridine tails that are longer than those in normal cells and lack a terminal 2',3' cyclic phosphate group. In mpn1Δ yeast cells, U6 snRNA and U4/U6 di-small nuclear RNA protein complex levels are diminished, leading to precursor messenger RNA splicing defects, which are reverted by expression of either yeast or human Mpn1 and by overexpression of U6. Recombinant hMpn1 is a 3'-to-5' RNA exonuclease that removes uridines from U6 3' ends, generating terminal 2',3' cyclic phosphates in vitro. Finally, U6 degradation rates increase in mpn1Δ yeasts and in lymphoblasts established from individuals affected by PN. Our data indicate that Mpn1 promotes U6 stability through 3' end posttranscriptional processing and implicate altered U6 metabolism as a potential mechanism for PN pathogenesis.
authors.affiliation: Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, Zürich, CH-8093, Switzerland.
authors.forename: Vadim
authors.initials: V
authors.lastname: Shchepachev
authors.forename: Harry
authors.initials: H
authors.lastname: Wischnewski
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.forename: Charlotte
authors.initials: C
authors.lastname: Soneson
authors.forename: Claus M
authors.initials: CM
authors.lastname: Azzalin
mesh_terms: D002460:Cell Line; D005092:Exonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009503:Neutropenia / Q000378:metabolism / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D012342:RNA, Small Nuclear / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology / Q000378:metabolism; D012868:Skin Abnormalities / Q000378:metabolism / Q000473:pathology
chemical_list: D012342:RNA, Small Nuclear; D011994:Recombinant Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; C405486:U6 small nuclear RNA; D005092:Exonucleases; D010727:Phosphoric Diester Hydrolases; C576020:USB1 protein, human