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A cancer-specific ubiquitin ligase drives alternative polyadenylation by targeting PCF11

ABSTRACT: A cancer-specific ubiquitin ligase drives alternative polyadenylation by targeting PCF11

PROVIDER: PRJNA556709 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9837040_1.fastq.gz	Fastqsanger.gz
	SRR9837040_2.fastq.gz	Fastqsanger.gz
	SRR9837050_1.fastq.gz	Fastqsanger.gz
	SRR9837050_2.fastq.gz	Fastqsanger.gz
	SRR9837060_1.fastq.gz	Fastqsanger.gz

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A cancer-specific ubiquitin ligase drives alternative polyadenylation by targeting PCF11

Project description:Alternative polyadenylation (APA) contributes to the complexity of the transcriptome by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3'-US) of mRNAs is a common feature of most cancer cells. However, the molecular mechanisms promoting APA in cancer are not well established. Here, we describe a widespread mechanism promoting 3'-US in cancer through ubiquitination and degradation of the 3' processing complex protein, PCF11, by the cancer-specific MAGE-A11-HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in human cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11 for degradation. This leads to APA of many transcripts in ovarian and lung tumors from both mouse xenografts and human tumor specimens. Importantly, expression of a non-degradable PCF11 degron mutant suppressed MAGE-A11 oncogenic activity and 3'-US. Analysis of the transcripts affected by MAGE-A11, revealed core oncogenic and tumor suppressor genes and pathways. This includes 3'-US of the cyclin D2 oncogene leading to deregulation of the Rb tumor suppressor pathway. Furthermore, competing endogenous RNA (ceRNA) partners of 3'-US transcripts include many tumor suppressor genes, such as PTEN that is downregulated by MAGE-A11 resulting in activation of the Akt growth signaling pathway. These findings provide insights into the function of MAGE-A11 and help explain the molecular mechanisms driving APA in cancer.

2020-01-22 | GSE134898 | GEO

Mouse alternative polyadenylation

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The 3' end processing factor PCF11 regulates gene expression based on gene size and intronic polyadenylation

Project description:Genes with different sizes have distinct expression patterns and functions. Here we show that the 3' end processing PCF11 modulates gene expression according to gene size. Gene density and polyA site strength, but not orientation between neighboring genes, impact short gene regulation by PCF11. In contrast, long gene modulation involves intronic polyadenylation (IPA), which is widespread in large introns. Downregulation of PCF11, which takes place in cell differentiation, contributes to short and long gene expressions with functions related to cell proliferation, cell morphology, adhesion, and migration. Mild, exogenous upregulation of PCF11 perturbs the gene expression program in cell differentiation. Further, PCF11 is auto-regulated through a highly conserved IPA site, the removal of which leads to PCF11 overexpression and global activation of proximal PASs sites. Together, our data indicate that PCF11 level impacts gene expression based on size and its autoregulation maintains homeostasis of PAS usage in the cell.

2019-02-12 | GSE115232 | GEO

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

Project description:Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects. HeLa cell line was stably transfected with shRNA plasmids targeting CstF64. Total RNA was isolated from CstF64 KD cells and wild-type control cells using Trizol according to manufacturerâs protocols. Samples were deep sequenced in duplicate using the Illumina GAIIx system.

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Ubiquitin ligase COP1 suppresses microglia-mediated inflammation

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Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

2016-03-14 | GSE79157 | GEO

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

Project description:We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects. Hematopoietic stem cells (HSC) from the bone marrow of transgenic animals carrying a N-myc/mCherry fusion gene were sorted according to N-myc expression (defined by mCherry) into N-myc high and low subpopulations. Each of these 2 populations was subjected to microarray gene expression profiling.

2016-08-20 | E-GEOD-85832 | biostudies-arrayexpress

E3 ligase SYVN1-Mediated Polyubiquitination of CPSF6 Promotes Alternative Polyadenylation and Antivirus Effects of Macrophages

Project description:E3 ligase SYVN1-Mediated Polyubiquitination of CPSF6 Promotes Alternative Polyadenylation and Antivirus Effects of Macrophages

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A cancer-specific ubiquitin ligase drives alternative polyadenylation by targeting PCF11

Project description:Quantitative proteomic analysis of MAGEA11 DAOY cells with or without re-expression of MAGEA11, using multiplex tandem mass tag (TMT) labeling, combined with two dimensional liquid chromatography for extensive peptide fractionation, and tandem mass spectrometry for peptide/protein identification and quantification (TMT-LC/LC-MS/MS).

2019-07-23 | MSV000084123 | MassIVE

CRL4(CRBN) ubiquitin ligase profiling

Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN).

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