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Eukaryotic Initiation factor 4B is a multi-functional RNA binding protein that regulates histone mRNAs

ABSTRACT: In diffuse large B-cell lymphoma (DLBCL) poor outcome is associated with EIF4B-dependent stimulation of the DEAD box helicase eIF4A that unwinds RNA structures in 5’ untranslated regions (UTRs) in mRNAs that encode proteins with a role in cell proliferation. We carried out iCLIP to examine differences in RNAs bound by eIF4B in DLBCL-derived- versus control B-cells and show that eIF4B bound ~10-fold more mRNAs in DLBCL-derived cells. In addition to interacting with 5' UTRs we unexpectedly find that eIF4B binds across the entire mRNA transcripts, with mutually exclusive, position-dependent binding related to different functional protein groups. Interestingly, there was an enrichment for binding within the 3’ UTR of mRNAs encoding replication-dependent histones, and consistent with this, we find that eIF4B interacts with UPF1, a helicase that plays a key role in the turnover of histone mRNAs at the end of S-phase. We identify a direct role for eIF4B in the turnover of histone mRNAs and demonstrate that eIF4B contributes to regulated cell cycle progression through controlling the translation and turnover of selected mRNAs.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): Lymphoma

SUBMITTER: Robert Harvey

LAB HEAD: Anne Willis

PROVIDER: PXD042538 | Pride | 2024-09-04

REPOSITORIES: Pride

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			Action	DRS
	GG_DoHH2_IgG_A_061218001.raw.zip	Raw
	GG_DoHH2_IgG_A_061218002.raw.zip	Raw
	GG_DoHH2_IgG_A_061218003.raw.zip	Raw
	GG_DoHH2_IgG_A_061218004.raw.zip	Raw
	GG_DoHH2_IgG_A_061218005.raw.zip	Raw

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Project description:DEAD-box RNA helicases eIF4A and Ded1 are believed to promote translation initiation by resolving mRNA secondary structures that impede ribosome attachment at the mRNA 5’ end or subsequent scanning of the 5’UTR, but whether they perform distinct functions or act redundantly in vivo is poorly understood. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling. Despite similar reductions in bulk translation, inactivation of a cold-sensitive Ded1 mutant substantially reduced the TEs of >600 mRNAs, whereas inactivation of a temperature-sensitive eIF4A mutant yielded <40 similarly impaired mRNAs. The broader requirement for Ded1 did not reflect more pervasive secondary structures at low temperature, as inactivation of temperature-sensitive and cold-sensitive ded1 mutants gave highly correlated results. Interestingly, Ded1-dependent mRNAs exhibit greater than average 5’UTR length and propensity for secondary structure, implicating Ded1 in scanning though structured 5' UTRs. Reporter assays confirmed that cap- distal stem-loop insertions increase dependence on Ded1 but not eIF4A for efficient translation. While only a small fraction of mRNAs is strongly dependent on eIF4A, this dependence is significantly correlated with requirements for Ded1 and 5’UTR features characteristic of Ded1- dependent mRNAs. Our findings suggest that Ded1 is critically required to promote scanning through secondary structures within 5’UTRs; and while eIF4A cooperates with Ded1 in this function, it also promotes a step of initiation common to virtually all yeast mRNAs. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling.The study includes 32 samples, comprised of 16 mRNA-Seq samples and 16 ribosome footprint profiling samples, derived from biological replicates of 3 mutant strains, ded1-cs, ded1-ts and tif1-ts, and the corresponding wild-type strains. The tif1-ts mutant and its wild-type counterpart were analyzed at 30°C and 37°C.

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Eukaryotic Initiation factor 4B is a multi-functional RNA binding protein that regulates histone mRNAs

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