1. XRN2 Links Transcription Termination to DNA Damage and Replication Stress.

    PLoS Genetics 12(7):e1006107 (2016) PMID 27437695 PMCID PMC4954731

    XRN2 is a 5'-3' exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclea...
  2. Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities.

    PNAS 112(34):E4726 (2015) PMID 26261309 PMCID PMC4553800

    Serine/arginine-rich splicing factor 2 (SRSF2) is an RNA-binding protein that plays important roles in splicing of mRNA precursors. SRSF2 mutations are frequently found in patients with myelodysplastic syndromes and certain leukemias, but how these mutations affect SRSF2 function has only begun ...
  3. ALS mutations in TLS/FUS disrupt target gene expression.

    Genes & Development 29(16):1696 (2015) PMID 26251528 PMCID PMC4561479

    Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ...
  4. SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3.

    Cell Reports 11(11):1694 (2015) PMID 26074071

    Protein synthesis is crucial for the maintenance of long-term-memory-related synaptic plasticity. The prion-like cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates the translation of several mRNAs important for long-term synaptic plasticity in the hippocampus. Here, we provi...
  5. Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.

    Genes & Development 29(12):1298 (2015) PMID 26080815 PMCID PMC4495400

    Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional tar...
  6. The end of the message: multiple protein-RNA interactions define the mRNA polyadenylation site.

    Genes & Development 29(9):889 (2015) PMID 25934501 PMCID PMC4421977

    The key RNA sequence elements and protein factors necessary for 3' processing of polyadenylated mRNA precursors are well known. Recent studies, however, have significantly reshaped current models for the protein-RNA interactions involved in poly(A) site recognition, painting a picture more compl...
  7. A journey to the end of the message.

    RNA 21(4):538 (2015) PMID 25780128 PMCID PMC4371270

  8. Systematic profiling of poly(A)+ transcripts modulated by core 3' end processing and splicing factors reveals regulatory rules of alternative cleavage and polyadenylation.

    PLoS Genetics 11(4):e1005166 (2015) PMID 25906188 PMCID PMC4407891

    Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3' untranslated regions (3'UTRs) and/or coding sequences. How core cleavage/polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found...
  9. Sumoylation controls the timing of Tup1-mediated transcriptional deactivation.

    Nature Communications 6:6610 (2015) PMID 25766875 PMCID PMC4360881

    The small ubiquitin-like modifier (SUMO) is implicated in various cellular activities, including transcriptional regulation. We previously showed that the yeast activator Gcn4 becomes sumoylated during activation, facilitating its eventual promoter eviction and transcriptional shut off. Here we ...
  10. cFLIP expression is altered in severe corticosteroid-resistant asthma.

    Genomics Data 2:99 (2014) PMID 26484081 PMCID PMC4535947

    Dysregulation of alternative splicing of mRNA precursors is known to contribute to numerous human diseases. In this study we carried out the first systematic search for asthma-associated changes in alternative splicing events, using a model of Aspergillus fumigatus (A. fumigatus)-sensitized mice...
  11. CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3' processing.

    Genes & Development 28(21):2370 (2014) PMID 25301780 PMCID PMC4215182

    AAUAAA is the most highly conserved motif in eukaryotic mRNA polyadenylation sites and, in mammals, is specifically recognized by the multisubunit CPSF (cleavage and polyadenylation specificity factor) complex. Despite its critical functions in mRNA 3' end formation, the molecular basis for CPSF...
  12. RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3' UTRs.

    Genes & Development 28(20):2248 (2014) PMID 25319826 PMCID PMC4201286

    Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3' processing in vitro and in vivo. RBBP6 as...
  13. New links between mRNA polyadenylation and diverse nuclear pathways.

    Molecules and Cells 37(9):644 (2014) PMID 25081038 PMCID PMC4179132

    The 3' ends of most eukaryotic messenger RNAs must undergo a maturation step that includes an endonuc-leolytic cleavage followed by addition of a polyadenylate tail. While this reaction is catalyzed by the action of only two enzymes it is supported by an unexpectedly large number of proteins. Th...
  14. Threonine-4 of the budding yeast RNAP II CTD couples transcription with Htz1-mediated chromatin remodeling.

    PNAS 111(33):11924 (2014) PMID 25071213 PMCID PMC4143052

    The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAP II) consists of repeated YSPTSPS heptapeptides and connects transcription with cotranscriptional events. Threonine-4 (Thr4) of the CTD repeats has been shown to function in histone mRNA 3'-end processing in chicken cel...
  15. Function and control of RNA polymerase II C-terminal domain phosphorylation in vertebrate transcription and RNA processing.

    Molecular and Cellular Biology 34(13):2488 (2014) PMID 24752900 PMCID PMC4054314

    The C-terminal domain of the RNA polymerase II largest subunit (the Rpb1 CTD) is composed of tandem heptad repeats of the consensus sequence Y(1)S(2)P(3)T(4)S(5)P(6)S(7). We reported previously that Thr 4 is phosphorylated and functions in histone mRNA 3'-end formation in chicken DT40 cells. Her...
  16. Delineating the structural blueprint of the pre-mRNA 3'-end processing machinery.

    Molecular and Cellular Biology 34(11):1894 (2014) PMID 24591651 PMCID PMC4019069

    Processing of mRNA precursors (pre-mRNAs) by polyadenylation is an essential step in gene expression. Polyadenylation consists of two steps, cleavage and poly(A) synthesis, and requires multiple cis elements in the pre-mRNA and a megadalton protein complex bearing the two essential enzymatic act...
  17. Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair.

    Nucleic Acids Research 42(8):4996 (2014) PMID 24589584 PMCID PMC4005673

    Functions of Kub5-Hera (In Greek Mythology Hera controlled Artemis) (K-H), the human homolog of the yeast transcription termination factor Rtt103, remain undefined. Here, we show that K-H has functions in both transcription termination and DNA double-strand break (DSB) repair. K-H forms distinct...
  18. Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation.

    Nucleic Acids Research 42(6):4019 (2014) PMID 24442672 PMCID PMC3973337

    Splicing factor SRSF10 is known to function as a sequence-specific splicing activator. Here, we used RNA-seq coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Moti...
  19. RNAP II CTD tyrosine 1 performs diverse functions in vertebrate cells.

    eLife 3:e02112 (2014) PMID 24842995 PMCID PMC4042873

    The RNA polymerase II largest subunit (Rpb1) contains a unique C-terminal domain (CTD) that plays multiple roles during transcription. The CTD is composed of consensus Y(1)S(2)P(3)T(4)S(5)P(6)S(7) repeats, in which Ser, Thr and Tyr residues can all be phosphorylated. Here we report analysis of C...
  20. SETX sumoylation: A link between DNA damage and RNA surveillance disrupted in AOA2.

    Rare Diseases 2:e27744 (2014) PMID 25054092 PMCID PMC4091563

    Senataxin (SETX) is a putative RNA:DNA helicase that is mutated in two distinct juvenile neurological disorders, AOA2 and ALS4. SETX is involved in the response to oxidative stress and is suggested to resolve R loops formed at transcription termination sites or at sites of collisions between the...