Aberrant 3′ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia

The recessive disorder poikiloderma with neutropenia (PN) is caused by mutations in the C16orf57 gene that encodes the highly conserved USB1 protein. Here, we present the 1.1 Å resolution crystal structure of human USB1, defining it as a member of the LigT-like superfamily of 2H phosphoesterases. We...

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Bibliographic Details
Published in:Blood 2013-02, Vol.121 (6), p.1028-1038
Main Authors: Hilcenko, Christine, Simpson, Paul J., Finch, Andrew J., Bowler, Frank R., Churcher, Mark J., Jin, Li, Packman, Len C., Shlien, Adam, Campbell, Peter, Kirwan, Michael, Dokal, Inderjeet, Warren, Alan J.
Format: Article
Language:English
Subjects:
3' Untranslated Regions - genetics
Adenine Nucleotides - genetics
Adenine Nucleotides - metabolism
Amino Acid Sequence
Base Sequence
Catalytic Domain
Cell Line
Crystallography, X-Ray
Genetic Complementation Test
Humans
Models, Genetic
Models, Molecular
Molecular Sequence Data
Mutation
Neutropenia - genetics
Neutropenia - metabolism
Oligoribonucleotides - genetics
Oligoribonucleotides - metabolism
Phosphoric Diester Hydrolases - chemistry
Phosphoric Diester Hydrolases - genetics
Phosphoric Diester Hydrolases - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Processing, Post-Transcriptional
RNA, Small Nuclear - genetics
RNA, Small Nuclear - metabolism
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - growth & development
Sequence Homology, Amino Acid
Skin Abnormalities - genetics
Skin Abnormalities - metabolism
Spliceosomes - genetics
Spliceosomes - metabolism
Uridine - genetics
Uridine - metabolism
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Summary:The recessive disorder poikiloderma with neutropenia (PN) is caused by mutations in the C16orf57 gene that encodes the highly conserved USB1 protein. Here, we present the 1.1 Å resolution crystal structure of human USB1, defining it as a member of the LigT-like superfamily of 2H phosphoesterases. We show that human USB1 is a distributive 3′-5′ exoribonuclease that posttranscriptionally removes uridine and adenosine nucleosides from the 3′ end of spliceosomal U6 small nuclear RNA (snRNA), directly catalyzing terminal 2′, 3′ cyclic phosphate formation. USB1 measures the appropriate length of the U6 oligo(U) tail by reading the position of a key adenine nucleotide (A102) and pausing 5 uridine residues downstream. We show that the 3′ ends of U6 snRNA in PN patient lymphoblasts are elongated and unexpectedly carry nontemplated 3′ oligo(A) tails that are characteristic of nuclear RNA surveillancetargets. Thus, our study reveals a novel quality control pathway in which posttranscriptional 3′-end processing by USB1 protects U6 snRNA from targeting and destruction by the nuclear exosome. Our data implicate aberrant oligoadenylation of U6 snRNA in the pathogenesis of the leukemia predisposition disorder PN. •Crystal structure of human USB1 identifies it as a member of the LigT-like superfamily of 2H phosphoesterases.•USB1 protects spliceosomal U6 small nuclear RNA from aberrant 3′ oligoadenylation.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2012-10-461491