Dataset Information

Widespread cancer relevant splicing events driven by the pRb-E2F pathway

ABSTRACT: E2F is a family of master transcription regulators involved in mediating diverse cell fates, and loss of control of the pathway is regarded as a hallmark of cancer. Recent studies have highlighted the pRb-E2F axis as a regulator of a large cellular network, which in addition to its classical target genes includes RNA splicing and non-coding genes. Here, we have addressed the generality of these effects by studying the role of the other key components of the pathway, including pRb, DP and PRMT5. Like E2F1, both pRb and DP1 influence transcription and alternative RNA splicing (AS) which is additionally impacted by PRMT5 activity. A detailed proteomics analysis of the E2F1 interactome revealed SRSF2 and HNRNPC as partner proteins that assist E2F1 in mediating the effects on RNA splicing. The ability of E2F1 to influence AS activity was apparent as cells progress through the cell cycle and during the DNA damage response. Our results highlight the role of the pRb-E2F pathway in mediating cell cycle regulation of gene expression mediated by transcription and RNA splicing, and provide a mechanistic understanding for how this is likely to occur.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: iolanda Vendrell

LAB HEAD: Nicholas B La Thangue

PROVIDER: PXD056505 | Pride | 2026-02-09

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	FL1340_MSQ2146_20210528_SCarr_E2F1_1_CR_2ul.raw	Raw
	FL1340_MSQ2146_20210528_SCarr_E2F1_2_CR_2ul.raw	Raw
	FL1340_MSQ2146_20210528_SCarr_E2F1_3_CR_2ul.raw	Raw
	FL1340_MSQ2146_20210528_SCarr_E2F1_4_WT.raw	Raw
	FL1340_MSQ2146_20210528_SCarr_E2F1_5_WT.raw	Raw

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Publications

Separate transcription and splicing gene networks are linked and coordinated by the pRb-E2F pathway.

Carr Simon M SM Liu Geng G Barczak Wojciech W Syffudin Hasan H Munro Shonagh S Reyna-Jeldes Denise D Vendrell Iolanda I Kessler Benedikt B Cribbs Adam P AP Kanapin Alexander A Samsonova Anastasia A La Thangue Nicholas B NB

Nucleic acids research 20260101 3

The pRb-E2F pathway is involved in mediating diverse cell fates, and oncogenic disruption of the pathway is regarded as a hallmark of cancer. Recent studies highlighted the pRb-E2F axis as a regulator of a large gene network which includes RNA splicing and transcription targets. Here, we have performed a deep genome-wide analysis of differentially expressed genes (DEGs) and alternatively spliced (AS) RNA targets which highlighted broadly non-overlapping networks of genes that are independently r ...[more]

PMID: 41614303

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Project description:The protein arginine methyl transferase PRMT5 is an enzyme expressed in oligodendrocyte lineage cells and responsible for the symmetric methylation of arginine residues on histone tails. Previous work from our laboratory identified PRMT5 as critical for myelination, due to its transcriptional regulation of survival and early stages of differentiation. However, besides its nuclear localization, PRMT5 is found at high levels in the cytoplasm of oligodendrocyte progenitor cells (OPCs) and yet, its interacting partners and non-histone substrates in this lineage, remain elusive. By using mass spectrometry on protein eluates from extracts generated from OPC and immunoprecipitated with PRMT5 antibodies, we identified 1116 proteins as PRMT5 interacting partners. These proteins are related to molecular functions such as RNA binding, ribosomal structure, nucleotide binding, cadherin and actin binding, GTP and GTPase activity. We then investigated PRMT5 substrates using iTRAQ-based proteomics on protein samples isolated from CRISPR-PRMT5 knockdown immortalized oligodendrocyte progenitors compared to CRISPR-EGFP controls. This analysis identified 169 peptides with statistically different symmetric methylation of arginine residues in the two groups. Those peptides led to 30 unique non-histone substrates of PRMT5. The majority of these proteins were consistent with PRMT5 substrates, previously identified in distinct cancer cell lines (e.g. the transcription factor ZN326), and were functionally related to RNA processing and transport, splicing, regulation of mRNA stability and transcription. In addition, we detected three substrates as unique to the oligodendrocyte lineage and not identified in cancer cells. They included the proline-rich protein PRC2C, involved in methyl-RNA binding, the RNA binding protein KHDR2, regulating splicing events and the heterogeneous nuclear RNA binding protein HNRPD, involved in regulation of RNA stability. Together, these results highlight a cell-specific role of PRMT5 in regulating, not only transcription, but RNA processing and translation in OPCs. (287 WORDS)