Dataset Information

5′ UTR length regulates the production of alternative N-terminal protein isoforms in health and disease

ABSTRACT: The 5′ untranslated region (5′ UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5′ UTR length also plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5′ UTRs enhance leaky scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. Changes in 5′ UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5′ UTR length, including a deletion in the VHL 5′ UTR in von Hippel–Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5′ UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding mutations can reshape the proteome.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Jimmy Ly

LAB HEAD: Iain Cheeseman

PROVIDER: PXD073007 | Pride | 2026-03-13

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20240905_Exploris_ES902_CFD_TMTIP_.mzML	Mzml
	20240905_Exploris_ES902_CFD_TMTIP_.mzid	Mzid
	20240905_Exploris_ES902_CheesemanLab_JL_CFD_1_2.raw	Raw
	20240905_Exploris_ES902_CheesemanLab_JL_CFD_3_4.raw	Raw
	20240905_Exploris_ES902_CheesemanLab_JL_CFD_5_6.raw	Raw

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5' UTR length regulates alternative N-terminal protein isoform production in health and disease.

Ly Jimmy J Smith Eric M EM Di Bernardo Matteo M Tao Yi Fei YF Black Elizabeth M EM Khalizeva Ekaterina E Cheeseman Iain M IM

bioRxiv : the preprint server for biology 20260120

The 5' untranslated region (5' UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5' UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5' UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that ...[more]

PMID: 41648370

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