Combinatorial control of Spo11 alternative splicing by modulation of RNA polymerase II dynamics and splicing factor recruitment during meiosis

AbstractThe heptad repeating sequence of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II is highly conserved in eukaryotes. In yeast, a CTD code consisting of pairs of heptad repeats is essential for viability. However, the strict requirement of diheptad repeats for the CTD function in transcription and splicing is unexplained. Here we show that CoAA (gene symbol RBM14), an oncoprotein and mammalian transcriptional coactivator, possesses diheptad repeats and directly interacts with the CTD. CoAA comprises 27 copies of tyrosine-rich repeats and regulates pre-mRNA synthesis and alternative splicing. Tyrosine substitutions in either the CoAA repeats or the CTD repeats diminish their interactions. Ser2- or Ser5-phosphorylated CTD peptides exhibit higher binding affinity to CoAA than the corresponding non-phosphorylated CTD peptide. CoAA dynamically interacts with both the CTD and hnRNP M, which is an alternative splicing regulator also comprising diheptad repeats. Arginine methylation of CoAA switches its interaction from the hnRNP M repeats to the CTD repeats. This study provides a mechanism for CoAA at the interface of transcription and alternative splicing, and explains the functional requirement of diheptad repeats in the CTD. In the human genome, tyrosine-rich repeats similar to the CoAA repeats were only found in six oncoproteins including EWS and SYT. We suggest that the diheptad sequence is one of the signature features for the CTD interaction among oncoproteins involved in transcription and alternative splicing. We anticipate that direct RNA Pol II interaction is a mechanism in oncogenesis.

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A Slow RNA Polymerase II Affects Alternative Splicing In Vivo

Molecular Cell ◽

10.1016/j.molcel.2003.08.001 ◽

2003 ◽

Vol 12 (2) ◽

pp. 525-532 ◽

Cited By ~ 424

Author(s):

Manuel de la Mata ◽

Claudio R Alonso ◽

Sebastián Kadener ◽

Juan P Fededa ◽

Matı́as Blaustein ◽

...

Keyword(s):

Alternative Splicing ◽

Rna Polymerase ◽

Rna Polymerase Ii

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DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II Elongation

Cell ◽

10.1016/j.cell.2009.09.022 ◽

2009 ◽

Vol 139 (1) ◽

pp. 211

Author(s):

Manuel J. Muñoz ◽

M. Soledad Pérez Santangelo ◽

Maria P. Paronetto ◽

Manuel de la Mata ◽

Federico Pelisch ◽

...

Keyword(s):

Dna Damage ◽

Alternative Splicing ◽

Rna Polymerase ◽

Rna Polymerase Ii

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Faculty Opinions recommendation of RNA polymerase II C-terminal domain mediates regulation of alternative splicing by SRp20.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1046774.505716 ◽

2006 ◽

Author(s):

Reinhard Lührmann

Keyword(s):

Alternative Splicing ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Terminal Domain

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The Transcription Elongation Factor CA150 Interacts with RNA Polymerase II and the Pre-mRNA Splicing Factor SF1

Molecular and Cellular Biology ◽

10.1128/mcb.21.22.7617-7628.2001 ◽

2001 ◽

Vol 21 (22) ◽

pp. 7617-7628 ◽

Cited By ~ 93

Author(s):

Aaron C. Goldstrohm ◽

Todd R. Albrecht ◽

Carles Suñé ◽

Mark T. Bedford ◽

Mariano A. Garcia-Blanco

Keyword(s):

Rna Polymerase ◽

Rna Polymerase Ii ◽

Transcription Elongation ◽

Elongation Factor ◽

Mrna Splicing ◽

Splicing Factor ◽

Nascent Transcript ◽

Ww Domains ◽

Transcription Elongation Factor ◽

Carboxyl Terminal

ABSTRACT CA150 represses RNA polymerase II (RNAPII) transcription by inhibiting the elongation of transcripts. The FF repeat domains of CA150 bind directly to the phosphorylated carboxyl-terminal domain of the largest subunit of RNAPII. We determined that this interaction is required for efficient CA150-mediated repression of transcription from the α4-integrin promoter. Additional functional determinants, namely, the WW1 and WW2 domains of CA150, were also required for efficient repression. A protein that interacted directly with CA150 WW1 and WW2 was identified as the splicing-transcription factor SF1. Previous studies have demonstrated a role for SF1 in transcription repression, and we found that binding of the CA150 WW1 and WW2 domains to SF1 correlated exactly with the functional contribution of these domains for repression. The binding specificity of the CA150 WW domains was found to be unique in comparison to known classes of WW domains. Furthermore, the CA150 binding site, within the carboxyl-terminal half of SF1, contains a novel type of proline-rich motif that may be recognized by the CA150 WW1 and WW2 domains. These results support a model for the recruitment of CA150 to repress transcription elongation. In this model, CA150 binds to the phosphorylated CTD of elongating RNAPII and SF1 targets the nascent transcript.

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Spliceosome disassembly factors ILP1 and NTR1 promote miRNA biogenesis in Arabidopsis thaliana

Nucleic Acids Research ◽

10.1093/nar/gkz526 ◽

2019 ◽

Vol 47 (15) ◽

pp. 7886-7900 ◽

Cited By ~ 3

Author(s):

Junli Wang ◽

Susu Chen ◽

Ning Jiang ◽

Ning Li ◽

Xiaoyan Wang ◽

...

Keyword(s):

Arabidopsis Thaliana ◽

Alternative Splicing ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Promoter Activity ◽

Mirna Biogenesis ◽

Stable Complex ◽

Transcriptional Elongation ◽

Related Protein

Abstract The intron-lariat spliceosome (ILS) complex is highly conserved among eukaryotes, and its disassembly marks the end of a canonical splicing cycle. In this study, we show that two conserved disassembly factors of the ILS complex, Increased Level of Polyploidy1-1D (ILP1) and NTC-Related protein 1 (NTR1), positively regulate microRNA (miRNA) biogenesis by facilitating transcriptional elongation of MIRNA (MIR) genes in Arabidopsis thaliana. ILP1 and NTR1 formed a stable complex and co-regulated alternative splicing of more than a hundred genes across the Arabidopsis genome, including some primary transcripts of miRNAs (pri-miRNAs). Intriguingly, pri-miRNAs, regardless of having introns or not, were globally down-regulated when the ILP1 or NTR1 function was compromised. ILP1 and NTR1 interacted with core miRNA processing proteins Dicer-like 1 and Serrate, and were required for proper RNA polymerase II occupancy at elongated regions of MIR chromatin, without affecting either MIR promoter activity or pri-miRNA decay. Our results provide further insights into the regulatory role of spliceosomal machineries in the biogenesis of miRNAs.

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