Upregulation of 5′-terminal oligopyrimidine mRNA translation upon loss of the ARF tumor suppressor

Cottrell, Kyle A.; Chiou, Ryan C.; Weber, Jason D.

doi:10.1038/s41598-020-79379-8

Cited by 5 publications

(4 citation statements)

References 54 publications

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“…Recent work has implicated additional oncogenic pathways in regulating 5 0 TOP-specific translational control. In particular, loss of the tumor suppressor Arf promotes the translation of 5 0 TOPcontaining mRNAs, implicating other pathways that act alongside mTOR signaling to promote expression of pro-growth protein repertoire (Cottrell et al, 2020).…”

Section: Sequence Features/motifsmentioning

confidence: 99%

Protein synthesis control in cancer: selectivity and therapeutic targeting

2022

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Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how cancer cells modulate the translational machinery to rapidly and selectively synthesize proteins in response to internal oncogenic demands and external factors in the tumor microenvironment. We highlight the clinical potential of compounds that target different translation factors as anti-cancer therapies. Next, we detail how RNA sequence and structural elements interface with the translational machinery and RNA-binding proteins to coordinate the translation of specific pro-survival and pro-growth programs. Finally, we provide an overview of the current and emerging technologies that can be used to illuminate the mechanisms of selective translational control in cancer cells as well as within the microenvironment.

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Section: Sequence Features/motifsmentioning

confidence: 99%

Protein synthesis control in cancer: selectivity and therapeutic targeting

2022

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“…The PI3K–Akt–mTOR signaling pathway modulates 5′TOP mRNA interactions with effector proteins and enhances their translation 6 – 11 , 45 , 61 . Loss of the tumor suppressor p53 was found to enhance 5′TOP mRNA translation through mTORC1 signaling 62 . DNA damage-responsive Myc signaling was also associated with the regulation of transcript metabolism.…”

Section: Discussionmentioning

confidence: 99%

Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

Wragg,

White,

Hadzhiev

et al. 2023

Nat Struct Mol Biol

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Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5′ terminal oligopyrimidine (5′TOP) sequence, dramatically increasing the range of genes potentially subjected to 5′TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K–Akt–mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.

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“…Terminal oligopyrimidine motif-containing mRNAs (TOPs) begin with a +1 cytidine nucleotide followed by 4-15 pyrimidines and encode all ribosomal proteins in mammals (1). For decades, it has been known that TOP translation is acutely regulated to coordinate ribosomal protein synthesis with demand across diverse cellular contexts (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) in a manner wholly dependent on the TOP motif at the 5'-end (12)(13)(14). These findings ultimately led to the identification of La-related protein 1 (LARP1) -a multi-domain evolutionarily-conserved RNA binding protein (15) -as a key regulator that directly binds to the TOP motif (16)(17)(18)(19).…”

Section: Main Textmentioning

confidence: 99%

LARP1 senses free ribosomes to coordinate supply and demand of ribosomal proteins

Saba,

Huang,

Schole

et al. 2023

Preprint

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Terminal oligopyrimidine motif-containing mRNAs (TOPs) encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies implicate LARP1 in 40S- or 80S-ribosome complexes that repress and stabilize TOPs. However, a mechanistic understanding of how LARP1 and TOPs interact with these complexes to coordinate TOP outcomes is lacking. Here, we show that LARP1 senses the cellular supply of ribosomes by directly binding non-translating ribosomal subunits. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the 40S mRNA channel. Free cytosolic ribosomes induce sequestration of TOPs in repressed 80S-LARP1-TOP complexes independent of alterations in mTOR signaling. Together, this work demonstrates a general ribosome-sensing function of LARP1 that allows it to tune ribosome protein synthesis to cellular demand.One-Sentence SummaryLARP1 directly binds free ribosomal subunits to repress TOP mRNAs

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Upregulation of 5′-terminal oligopyrimidine mRNA translation upon loss of the ARF tumor suppressor

Cited by 5 publications

References 54 publications

Protein synthesis control in cancer: selectivity and therapeutic targeting

Protein synthesis control in cancer: selectivity and therapeutic targeting

Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

LARP1 senses free ribosomes to coordinate supply and demand of ribosomal proteins

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