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Article ; Online: The unusual gene architecture of polyubiquitin is created by dual-specific splice sites.

Duan, Chaorui / Mooney, Truman / Buerer, Luke / Bowers, Cory / Rong, Stephen / Kim, Seong Won / Fredericks, Alger M / Monaghan, Sean F / Fairbrother, William G

Genome biology

2024 Volume 25, Issue 1, Page(s) 33

Abstract: Background: The removal of introns occurs through the splicing of a 5' splice site (5'ss) with a 3' splice site (3'ss). These two elements are recognized by distinct components of the spliceosome. However, introns in higher eukaryotes contain many ... ...

Abstract	Background: The removal of introns occurs through the splicing of a 5' splice site (5'ss) with a 3' splice site (3'ss). These two elements are recognized by distinct components of the spliceosome. However, introns in higher eukaryotes contain many matches to the 5' and 3' splice-site motifs that are presumed not to be used. Results: Here, we find that many of these sites can be used. We also find occurrences of the AGGT motif that can function as either a 5'ss or a 3'ss-previously referred to as dual-specific splice sites (DSSs)-within introns. Analysis of the Sequence Read Archive reveals a 3.1-fold enrichment of DSSs relative to expectation, implying synergy between the ability to function as a 5'ss and 3'ss. Despite this suggested mechanistic advantage, DSSs are 2.7- and 4.7-fold underrepresented in annotated 5' and 3' splice sites. A curious exception is the polyubiquitin gene UBC, which contains a tandem array of DSSs that precisely delimit the boundary of each ubiquitin monomer. The resulting isoforms splice stochastically to include a variable number of ubiquitin monomers. We found no evidence of tissue-specific or feedback regulation but note the 8.4-fold enrichment of DSS-spliced introns in tandem repeat genes suggests a driving role in the evolution of genes like UBC. Conclusions: We find an excess of unannotated splice sites and the utilization of DSSs in tandem repeats supports the role of splicing in gene evolution. These findings enhance our understanding of the diverse and complex nature of the splicing process.
MeSH term(s)	Polyubiquitin/genetics ; Introns ; RNA Splicing ; RNA Splice Sites ; Archives
Chemical Substances	Polyubiquitin (120904-94-1) ; RNA Splice Sites
Language	English
Publishing date	2024-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-023-03157-8
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Article ; Online: Mutational bias and the protein code shape the evolution of splicing enhancers.

Rong, Stephen / Buerer, Luke / Rhine, Christy L / Wang, Jing / Cygan, Kamil J / Fairbrother, William G

Nature communications

2020 Volume 11, Issue 1, Page(s) 2845

Abstract: Exonic splicing enhancers (ESEs) are enriched in exons relative to introns and bind splicing activators. This study considers a fundamental question of co-evolution: How did ESE motifs become enriched in exons prior to the evolution of ESE recognition? ... ...

Abstract	Exonic splicing enhancers (ESEs) are enriched in exons relative to introns and bind splicing activators. This study considers a fundamental question of co-evolution: How did ESE motifs become enriched in exons prior to the evolution of ESE recognition? We hypothesize that the high exon to intron motif ratios necessary for ESE function were created by mutational bias coupled with purifying selection on the protein code. These two forces retain certain coding motifs in exons while passively depleting them from introns. Through the use of simulations, genomic analyses, and high throughput splicing assays, we confirm the key predictions of this hypothesis, including an overlap between protein and splicing information in ESEs. We discuss the implications of mutational bias as an evolutionary driver in other cis-regulatory systems.
MeSH term(s)	Computer Simulation ; Enhancer Elements, Genetic ; Evolution, Molecular ; Exons/genetics ; Genome, Human ; Genomics ; High-Throughput Screening Assays ; Humans ; Introns/genetics ; Models, Genetic ; Mutation ; RNA Splicing
Language	English
Publishing date	2020-06-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-16673-z
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Article ; Online: Efficient Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from Exhaled Breath.

Duan, Chaorui / Buerer, Luke / Wang, Jing / Kaplan, Samuel / Sabalewski, Gavin / Jay, Gregory D / Monaghan, Sean F / Arena, Andrea E / Fairbrother, William G

The Journal of molecular diagnostics : JMD

2021 Volume 23, Issue 12, Page(s) 1661–1670

Abstract: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is transmitted through airborne particles in exhaled breath, causing severe respiratory disease, coronavirus disease-2019 (COVID-19), in some patients. Samples for SARS-CoV-2 testing are ... ...

Abstract	Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is transmitted through airborne particles in exhaled breath, causing severe respiratory disease, coronavirus disease-2019 (COVID-19), in some patients. Samples for SARS-CoV-2 testing are typically collected by nasopharyngeal swab, with the virus detected by PCR; however, patients can test positive for 3 months after infection. Without the capacity to assay SARS-CoV-2 in breath, it is not possible to understand the risk for transmission from infected individuals. To detect virus in breath, the Bubbler-a breathalyzer that reverse-transcribes RNA from SARS-CoV-2 particles into a sample-specific barcoded cDNA-was developed. In a study of 70 hospitalized patients, the Bubbler was both more predictive of lower respiratory tract involvement (abnormal chest X-ray) and less invasive than alternatives. Samples tested using the Bubbler were threefold more enriched for SARS-CoV-2 RNA than were samples from tongue swabs, implying that virus particles were being directly sampled. The barcode-enabled Bubbler was used for simultaneous diagnosis in large batches of pooled samples at a lower limit of detection of 334 genomic copies per sample. Diagnosis by sequencing can provide additional information, such as viral load and strain identity. The Bubbler was configured to sample nucleic acids in water droplets circulating in air, demonstrating its potential in environmental monitoring and the protective effect of adequate ventilation.
MeSH term(s)	Body Fluids/virology ; COVID-19/diagnosis ; COVID-19/virology ; COVID-19 Testing/methods ; Diagnostic Tests, Routine/methods ; Humans ; RNA, Viral/genetics ; Respiratory System/virology ; SARS-CoV-2/genetics ; Specimen Handling ; Viral Load/methods
Chemical Substances	RNA, Viral
Language	English
Publishing date	2021-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2021.09.005
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Article ; Online: Activation of human RNA lariat debranching enzyme Dbr1 by binding protein TTDN1 occurs though an intrinsically disordered C-terminal domain.

Clark, Nathaniel E / Katolik, Adam / Gallant, Pascal / Welch, Anastasia / Murphy, Eileen / Buerer, Luke / Schorl, Christoph / Naik, Nandita / Naik, Mandar T / Holloway, Stephen P / Cano, Kristin / Weintraub, Susan T / Howard, Katherine M / Hart, P John / Jogl, Gerwald / Damha, Masad J / Fairbrother, William G

The Journal of biological chemistry

2023 Volume 299, Issue 9, Page(s) 105100

Abstract: In eukaryotic cells, the introns are excised from pre-mRNA by the spliceosome. These introns typically have a lariat configuration due to the 2'-5' phosphodiester bond between an internal branched residue and the 5' terminus of the RNA. The only enzyme ... ...

Abstract	In eukaryotic cells, the introns are excised from pre-mRNA by the spliceosome. These introns typically have a lariat configuration due to the 2'-5' phosphodiester bond between an internal branched residue and the 5' terminus of the RNA. The only enzyme known to selectively hydrolyze the 2'-5' linkage of these lariats is the RNA lariat debranching enzyme Dbr1. In humans, Dbr1 is involved in processes such as class-switch recombination of immunoglobulin genes, and its dysfunction is implicated in viral encephalitis, HIV, ALS, and cancer. However, mechanistic details of precisely how Dbr1 affects these processes are missing. Here we show that human Dbr1 contains a disordered C-terminal domain through sequence analysis and nuclear magnetic resonance. This domain stabilizes Dbr1 in vitro by reducing aggregation but is dispensable for debranching activity. We establish that Dbr1 requires Fe
MeSH term(s)	Humans ; Introns ; RNA Nucleotidyltransferases/genetics ; RNA Nucleotidyltransferases/metabolism ; RNA Splicing ; Adaptor Proteins, Signal Transducing/metabolism ; Enzyme Activation/genetics ; Protein Domains ; Protein Binding ; Intrinsically Disordered Proteins/genetics ; Intrinsically Disordered Proteins/metabolism ; Entamoeba histolytica/enzymology ; Entamoeba histolytica/genetics ; Metals, Heavy/metabolism
Chemical Substances	Dbr1 protein, human (EC 2.7.7.-) ; RNA Nucleotidyltransferases (EC 2.7.7.-) ; MPLKIP protein, human ; Adaptor Proteins, Signal Transducing ; Intrinsically Disordered Proteins ; Metals, Heavy
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105100
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Article: The debranching enzyme Dbr1 regulates lariat turnover and intron splicing.

Buerer, Luke / Clark, Nathaniel E / Welch, Anastasia / Duan, Chaorui / Taggart, Allison J / Townley, Brittany A / Wang, Jing / Soemedi, Rachel / Rong, Stephen / Lin, Chien-Ling / Zeng, Yi / Katolik, Adam / Staley, Jonathan P / Damha, Masad J / Mosammaparast, Nima / Fairbrother, William G

Research square

2023

Abstract: The majority of genic transcription is intronic. Introns are removed by splicing as branched lariat RNAs which require rapid recycling. The branch site is recognized during splicing catalysis and later debranched by Dbr1 in the rate-limiting step of ... ...

Abstract	The majority of genic transcription is intronic. Introns are removed by splicing as branched lariat RNAs which require rapid recycling. The branch site is recognized during splicing catalysis and later debranched by Dbr1 in the rate-limiting step of lariat turnover. Through generation of the first viable
Language	English
Publishing date	2023-06-13
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2931976/v1
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Article ; Online: Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes.

Rhine, Christy L / Neil, Christopher / Wang, Jing / Maguire, Samantha / Buerer, Luke / Salomon, Mitchell / Meremikwu, Ijeoma C / Kim, Juliana / Strande, Natasha T / Fairbrother, William G

PLoS genetics

2022 Volume 18, Issue 1, Page(s) e1009884

Abstract: To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of ...

Abstract	To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5' splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical records of 3 ASD patients with TNRC6C variant revealed respiratory issues consistent with phenotypes observed in TNRC6 depleted mice. Overall, this study highlights the need for splicing analysis in determining variant pathogenicity, especially as it relates to ASD.
MeSH term(s)	Autism Spectrum Disorder/genetics ; Cell Line ; Exons ; Gene Regulatory Networks ; Genetic Predisposition to Disease ; Humans ; Mutation ; Pedigree ; Phenotype ; RNA Splicing ; RNA-Binding Proteins ; Silent Mutation
Chemical Substances	RNA-Binding Proteins ; TNRC6C protein, human
Language	English
Publishing date	2022-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1009884
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Article ; Online: Metal content and kinetic properties of yeast RNA lariat debranching enzyme Dbr1.

Clark, Nathaniel E / Katolik, Adam / Taggart, Allison J / Buerer, Luke / Holloway, Stephen P / Miller, Nathaniel / Phillips, John D / Farrell, Colin P / Damha, Masad J / Fairbrother, William G

RNA (New York, N.Y.)

2022 Volume 28, Issue 7, Page(s) 927–936

Abstract: In eukaryotic cells, intron lariats produced by the spliceosome contain a 2'5' phosphodiester linkage. The RNA lariat debranching enzyme, Dbr1, is the only enzyme known to hydrolyze this bond. Dbr1 is a member of the metallophosphoesterase (MPE) family ... ...

Abstract	In eukaryotic cells, intron lariats produced by the spliceosome contain a 2'5' phosphodiester linkage. The RNA lariat debranching enzyme, Dbr1, is the only enzyme known to hydrolyze this bond. Dbr1 is a member of the metallophosphoesterase (MPE) family of enzymes, and recent X-ray crystal structures and biochemistry data demonstrate that Dbr1 from
MeSH term(s)	Escherichia coli/genetics ; Escherichia coli/metabolism ; Humans ; Introns ; Metals ; RNA/chemistry ; RNA Nucleotidyltransferases/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism
Chemical Substances	Metals ; RNA (63231-63-0) ; Dbr1 protein, human (EC 2.7.7.-) ; RNA Nucleotidyltransferases (EC 2.7.7.-) ; lariat debranching enzyme (EC 2.7.7.-)
Language	English
Publishing date	2022-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079159.122
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Zs.A 4777: Show issues

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Article ; Online: A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy.

Molecular cell

2023 Volume 83, Issue 13, Page(s) 2258–2275.e11

Abstract: The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP- ...

Abstract	The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.
MeSH term(s)	Animals ; Mice ; Introns/genetics ; Trichothiodystrophy Syndromes/genetics ; RNA Nucleotidyltransferases/genetics ; RNA Splicing
Chemical Substances	lariat debranching enzyme (EC 2.7.7.-) ; RNA Nucleotidyltransferases (EC 2.7.7.-)
Language	English
Publishing date	2023-06-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.06.011
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Article ; Online: The unusual gene architecture of polyubiquitin is created by dual-specific splice sites.

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Article ; Online: Mutational bias and the protein code shape the evolution of splicing enhancers.

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Article ; Online: Efficient Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from Exhaled Breath.

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Article ; Online: Activation of human RNA lariat debranching enzyme Dbr1 by binding protein TTDN1 occurs though an intrinsically disordered C-terminal domain.

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Article: The debranching enzyme Dbr1 regulates lariat turnover and intron splicing.

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Article ; Online: Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes.

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Article ; Online: Metal content and kinetic properties of yeast RNA lariat debranching enzyme Dbr1.

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Article ; Online: A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy.

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