Interactome for auxiliary splicing factor U2AF65 suggests diverse roles

Prigge, Justin R.; Iverson, Sonya V.; Siders, Ashley M.; Schmidt, Edward E.

doi:10.1016/j.bbagrm.2009.06.002

Cited by 27 publications

(40 citation statements)

References 49 publications

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“…The U2 snRNP has SF3A1-A3 and SF3B1-B5. U2AF65 is a U2 snRNP auxiliary factor that is an essential component of the pre-mRNA splicing machinery (Prigge et al, 2009). regulators include KAT2B, HDAC1/2, SWI/SNF, CTCF, MeCP2, WDR5/MLL (an H3K4 methyltransferase), EZH2 (a repressor), and mediator , Sjolinder et al, 2005, Tyagi et al, 2009, Khan et al, 2012, Maxwell et al, 2013, Tsai et al, 2010, Gardini and Shiekhattar, 2015.…”

Section: H3k4me3 Readersmentioning

confidence: 99%

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

Davie

Delcuve

2016

Biochem. Cell Biol.

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Histone H3 lysine 4 trimethylation (H3K4me3) is often stated as a mark of transcriptionally active promoters. However, closer study of the positioning of H3K4me3 shows the mark locating primarily after the first exon at the 5' splice site and overlapping with a CpG island in mammalian cells. There are several enzyme complexes that are involved in the placement of the H3K4me3 mark, including multiple protein complexes containing SETD1A, SETD1B, and MLL1 enzymes (writers). CXXC1, which is associated with SETD1A and SETD1B, target these enzymes to unmethylated CpG islands. Lysine demethylases (KDM5 family members, erasers) demethylate H3K4me3. The H3K4me3 mark is recognized by several proteins (readers), including lysine acetyltransferase complexes, chromatin remodelers, and RNA bound proteins involved in pre-mRNA splicing. Interestingly, attenuation of H3K4me3 impacts pre-mRNA splicing, and inhibition of pre-mRNA splicing attenuates H3K4me3.

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Section: H3k4me3 Readersmentioning

confidence: 99%

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

Davie

Delcuve

2016

Biochem. Cell Biol.

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“…However, in the budding yeast Saccharomyces cerevisiae, the large subunit is dispensable and the small subunit is absent (1). In humans, U2AF65 interacts with several splicing factors (BBP/SF1, UAP56, SAP155 [or SF3b155], and p54) (1,14,19,43,45,70) and facilitates branch point recognition (2, 4). The mammalian U2AF65 is found to be dispensable for splicing of some introns in vitro in the presence of the SR protein SC35 (36).…”

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confidence: 99%

Genomic mRNA Profiling Reveals Compensatory Mechanisms for the Requirement of the Essential Splicing Factor U2AF

Sridharan

Heimiller

Singh

2011

Molecular and Cellular Biology

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The large subunit of the U2 auxiliary factor (U2AF) recognizes the polypyrimidine tract (Py-tract) located adjacent to the 3 splice site to facilitate U2 snRNP recruitment. While U2AF is considered essential for pre-mRNA splicing, its requirement for splicing on a genome-wide level has not been analyzed. Using Solexa sequencing, we performed mRNA profiling for splicing in the Schizosaccharomyces pombe U2AF 59 (prp2.1) temperature-sensitive mutant. Surprisingly, our analysis revealed that introns show a range of splicing defects in the mutant strain. While U2AF 59 inactivation (nonpermissive) conditions inhibit splicing of some introns, others are spliced apparently normally. Bioinformatics analysis indicated that U2AF 59 -insensitive introns have stronger 5 splice sites and higher A/U content. Most importantly, features that contribute to U2AF 59 insensitivity of an intron unexpectedly reside in its 5-most 30 nucleotides. These include the 5 splice site, a guanosine at position 7, and the 5 splice site-to-branch point sequence context. A differential requirement (similar to U2AF 59 ) for introns may also apply to other general splicing factors (e.g., prp10). Our combined results indicate that U2AF insensitivity is a common phenomenon and that varied intron features support the existence of unrecognized aspects of spliceosome assembly.Pre-mRNA splicing plays a major role in gene regulation (23). Furthermore, alternative splicing serves as an important mechanism to generate molecular diversity (5). In the initial stages of splicing, the U1 snRNP recognizes the 5Ј splice site (5Ј SS), and the U2 snRNP auxiliary factor (U2AF) recognizes the polypyrimidine tract (Py-tract)/3Ј splice site (3Ј SS), leading to U2 snRNP recruitment to the branch point sequence (BPS) (27).In humans, the essential splicing factor U2AF, which has been extensively studied, is a heterodimeric protein containing a large subunit (U2AF65) and a small subunit (U2AF35). These subunits bind to the Py-tract and the 3Ј SS, respectively (37,65,68,71). Both subunits of U2AF are essential for viability in many model organisms, such as zebrafish, the fruit fly, the nematode worm, and fission yeast Schizosaccharomyces pombe (U2AF59) (17,28,42,46,47,59,72). However, in the budding yeast Saccharomyces cerevisiae, the large subunit is dispensable and the small subunit is absent (1). In humans, U2AF65 interacts with several splicing factors (BBP/SF1, UAP56, SAP155 [or SF3b155], and p54) (1,14,19,43,45,70) and facilitates branch point recognition (2, 4). The mammalian U2AF65 is found to be dispensable for splicing of some introns in vitro in the presence of the SR protein SC35 (36). Microarray analyses revealed an unexpected role of the Drosophila melanogaster large subunit (dU2AF50) in the nuclear export of intronless mRNAs (8). Several splicing regulators, such as SXL, PTB, hnRNP A1, ASF/SF2, SC35, and TRA, can facilitate or antagonize U2AF activity for splicing regulation (5, 53).Biochemical and structural studies indicate that the essential splicing factor...

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“…It is of note that both U2af2 and Erh have been implicated in the regulation of RNA splicing [60, 61]. Furthermore, U2af2 interacts with Rbm39 in yeast-two hybrid assays [62]. In the current study, Rbm39 was also identified as a DEPDC1B-interacting protein.…”

Section: Discussionmentioning

confidence: 49%

Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2

Zhu

Jimenez-Cowell

et al. 2015

Experimental Cell Research

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Pitx2 is a bicoid-related homeobox transcription factor implicated in regulating left-right patterning and organogenesis. However, only a limited number of Pitx2 downstream target genes have been identified and characterized. Here we demonstrate that Pitx2 is a transcriptional repressor of DEP domain containing 1B (DEPDC1B). The first intron of the human and mouse DEP domain containing 1B genes contains multiple consensus DNA-binding sites for Pitx2. Chromatin immunoprecipitation assays revealed that Pitx2, along with histone deacetylase 1, was recruited to the first intron of Depdc1b. In contrast, RNAi-mediated depletion of Pitx2 not only enhanced the acetylation of histone H4 in the first intron of Depdc1b, but also increased the protein level of Depdc1b. Luciferase reporter assays also showed that Pitx2 could repress the transcriptional activity mediated by the first intron of human DEPDC1B. The GAP domain of DEPDC1B interacted with nucleotide-bound forms of RAC1 in vitro. In addition, exogenous expression of DEPDC1B suppressed RAC1 activation and interfered with actin polymerization induced by the guanine nucleotide exchange factor TRIO. Moreover, DEPDC1B interacted with various signaling molecules such as U2af2, Erh, and Salm. We propose that Pitx2-mediated repression of Depdc1b expression contributes to the regulation of multiple molecular pathways, such as Rho GTPase signaling.

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Interactome for auxiliary splicing factor U2AF65 suggests diverse roles

Cited by 27 publications

References 49 publications

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

Genomic mRNA Profiling Reveals Compensatory Mechanisms for the Requirement of the Essential Splicing Factor U2AF

Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2

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