A common germline 3′ UTR variant controls DDIT4 translation efficiency and stress responses in cancer cells

Systematic strategies for identifying and classifying variants that directly modulate ribosome engagement are lacking. Here, we develop and extensively validate a pipeline to identify translation-associated single-nucleotide polymorphisms (tranSNPs) by integrating analysis of total and polysome-associated mRNAs. Common variants showing allele-specific enrichment in polysomes, without corresponding changes in mRNA levels, were uncovered. We focused on rs1053639, a frequent germline SNP located in the 3′ UTR of DNA damage-inducible transcript 4 (DDIT4), a key negative regulator of mTORC1. Using edited cell models, we showed that this variant controls DDIT4 protein output. Mechanistically, the two rs1053639 alleles differ in their interaction with the RNA-binding protein RBMX, leading to altered mRNA subcellular localization and translation. Functionally, allele-specific regulation of DDIT4 translation impacts stress-dependent mTORC1 repression and autophagy, resulting in divergent competitive fitness in co-culture or xenograft assays and response to therapeutic perturbations. Analysis of cancer patient datasets revealed an association between rs1053639 genotype and clinical outcome in colorectal cancer.

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Publication Details

Journal
iScience
Published
2026-10-06
DOI
https://doi.org/10.1016/j.isci.2026.117707
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.00
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article

A common germline 3′ UTR variant controls DDIT4 translation efficiency and stress responses in cancer cells

Sara Zaccara, Alessandro Mattè, Meriem Hadjer Hamadou, Davide Dalfovo et al.
iScience
RNA Research and Splicing
article

A common germline 3′ UTR variant controls DDIT4 translation efficiency and stress responses in cancer cells

Sara Zaccara, Alessandro Mattè, Meriem Hadjer Hamadou, Davide Dalfovo, Alberto Inga, Giovanni Bertalot, Emilio Cusanelli, Stefano Freddi, Roberto Bertorelli, Alessandro Romanel, Samuel Valentini, Alessia Mattivi, Laura Alunno, Marina Mione, Michael Pancher, Luca L. Fava, Virginie Marcel, Veronica De Sanctis, Vincenza Vigorito, Glenda Paola Grupelli, Pamela Gatto, Tecla Venturelli, Francesca Lorenzini, Chiara Valentini
article en

Abstract

Systematic strategies for identifying and classifying variants that directly modulate ribosome engagement are lacking. Here, we develop and extensively validate a pipeline to identify translation-associated single-nucleotide polymorphisms (tranSNPs) by integrating analysis of total and polysome-associated mRNAs. Common variants showing allele-specific enrichment in polysomes, without corresponding changes in mRNA levels, were uncovered. We focused on rs1053639, a frequent germline SNP located in the 3′ UTR of DNA damage-inducible transcript 4 (DDIT4), a key negative regulator of mTORC1. Using edited cell models, we showed that this variant controls DDIT4 protein output. Mechanistically, the two rs1053639 alleles differ in their interaction with the RNA-binding protein RBMX, leading to altered mRNA subcellular localization and translation. Functionally, allele-specific regulation of DDIT4 translation impacts stress-dependent mTORC1 repression and autophagy, resulting in divergent competitive fitness in co-culture or xenograft assays and response to therapeutic perturbations. Analysis of cancer patient datasets revealed an association between rs1053639 genotype and clinical outcome in colorectal cancer.

iScienceVol. 29(11)
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), University of Milan (IT), University of Trento (IT), Columbia University Irving Medical Center (US), Centre de Recherche en Cancérologie de Lyon (FR), European Institute of Oncology (IT)
Good health and well-being
Openalex Percentile: Top 22%
RNA Research and Splicing
DOIOpen Access PDFOpenAlex
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