C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3' end modification.

Abstract

C16orf57 encodes a human protein of unknown function, and mutations in the gene occur in poikiloderma with neutropenia (PN), which is a rare, autosomal recessive disease. Interestingly, mutations in C16orf57 were also observed among patients diagnosed with Rothmund-Thomson syndrome (RTS) and dyskeratosis congenita (DC), which are caused by mutations in genes involved in DNA repair and telomere maintenance. A genetic screen in Saccharomyces cerevisiae revealed that the yeast ortholog of C16orf57, USB1 (YLR132C), is essential for U6 small nuclear RNA (snRNA) biogenesis and cell viability. Usb1 depletion destabilized U6 snRNA, leading to splicing defects and cell growth defects, which was suppressed by the presence of multiple copies of the U6 snRNA gene SNR6. Moreover, Usb1 is essential for the generation of a unique feature of U6 snRNA; namely, the 3'-terminal phosphate. RNAi experiments in human cells followed by biochemical and functional analyses confirmed that, similar to yeast, C16orf57 encodes a protein involved in the 2',3'-cyclic phosphate formation at the 3' end of U6 snRNA. Advanced bioinformatics predicted that C16orf57 encodes a phosphodiesterase whose putative catalytic activity is essential for its function in vivo. Our results predict an unexpected molecular basis for PN, DC, and RTS and provide insight into U6 snRNA 3' end formation.

• Authors: Seweryn Mroczek, Joanna Krwawicz, Jan Kutner, Michal Lazniewski, Iwo Kuciński, Krzysztof Ginalski, Andrzej Dziembowski
• Journal: Genes & development (Genes Dev) Vol. 26 Issue 17 Pg. 1911-25 (Sep 01 2012) ISSN: 1549-5477 [Electronic] United States
• PMID: 22899009 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mitochondrial Proteins
• RNA, Small Nuclear
• Saccharomyces cerevisiae Proteins
• U6 small nuclear RNA
• Usb1 protein, S cerevisiae
• Phosphoric Diester Hydrolases
• USB1 protein, human

Topics

• HEK293 Cells
• HeLa Cells
• Humans
• Mitochondrial Proteins (genetics, metabolism)
• Models, Molecular
• Mutation
• Neutropenia (enzymology, genetics)
• Phosphoric Diester Hydrolases (chemistry, genetics, metabolism)
• Protein Structure, Tertiary
• RNA 3' End Processing (genetics)
• RNA Interference
• RNA Stability (genetics)
• RNA, Small Nuclear (metabolism)
• Rothmund-Thomson Syndrome (enzymology, genetics)
• Saccharomyces cerevisiae (enzymology, genetics)
• Saccharomyces cerevisiae Proteins (genetics, metabolism)