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

DOI: 10.1182/blood-2012-10-461491 DOI Help
PMID: 23190533 PMID Help

Authors: Christine Hilcenko (Medical Research Council) , Paul Simpson (MRC Laboratory of Molecular Biology) , Adrian Finch (University of St Andrews) , F. R. Bowler , M. J. Churcher , L. Jin , L. C. Packman , A. Shlien , P. Campbell , M. Kirwan , I. Dokal , Anna Warren (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Blood , VOL 121 (6) , PAGES 1028 - 1038

State: Published (Approved)
Published: February 2013
Diamond Proposal Number(s): 8547

Abstract: 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.

Journal Keywords: Adenine; Amino; Base; Catalytic; Cell; Crystallography ; X-Ray ; Genetic; Humans ; Models ; Genetic ; Models ; Molecular ; Mutation ; Neutropenia ; Oligoribonucleotides ; Phosphoric; RNA; Post-Transcriptional ; RNA ; Small; Reverse; Saccharomyces; Sequence; Amino; Skin; Spliceosomes ; Uridine

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

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