Search
Search articles by title, abstract,author or doi
Advanced search

A codon-specific decoding program by oncogenic RAS signaling

Rongrong He , Shu-Bing Qian

Vita ››

PDF (1410KB)
Vita > Cutting Edge > DOI: 10.15302/vita.2026.07.0052
Vita Open AccessPublished:

A codon-specific decoding program by oncogenic RAS signaling

Author information +
History +
Vita () Cite this article
PDF (1410KB)

Oncogenic RAS-MAPK signaling is best known as a phosphorylation cascade. Reporting in Vita, Xing et al. uncover an unexpected translational output of this pathway: an RSK-METTL13-eEF1A axis that accelerates decoding of the rare arginine codon CGA, thereby boosting the synthesis of proteins that promote cell growth and drug resistance, revealing METTL13 as a potential therapeutic target in RAS-driven cancers.

登录浏览全文

4963

注册一个新账户 忘记密码

Activating mutations in the RAS-MAPK pathway occur in more than 40% of human cancers and drive some of the most lethal malignancies1. The emergence of covalent KRAS-mutant and pan-RAS inhibitors has marked a major therapeutic advance1, yet their clinical benefit is often limited by adaptive resistance. Because drug resistance can arise through diverse genetic and signaling routes — including secondary RAS mutations, feedback reactivation of upstream kinases and compensatory signaling pathways2,3 — a central question remains: what downstream machinery enables RAS-driven tumors to sustain growth despite pathway inhibition? Regardless of the mechanism, resistant cancer cells must maintain protein synthesis to survive treatment. In this issue, Xing et al.4 provide an unexpected answer: rather than simply increasing global translation, oncogenic RAS selectively accelerates decoding of the rare arginine codon CGA, thereby boosting the synthesis of proteins that promote proliferation and drug tolerance.
Using ribosome profiling across epithelial cells transformed by distinct oncogenic drivers, the authors found that reduced A-site ribosome occupancy at CGA — a hallmark of fast decoding — was a unique feature of RAS-MAPK activation. Integrated translatome and proteome analyses further revealed that CGA-enriched transcripts exhibited increased translation efficiency and protein abundance in MCF10A cells expressing KRASG12D. These transcripts encode ribosomal proteins, RNA splicing factors, cell-cycle regulators, and mitochondrial proteins, forming a functionally coherent, codon-defined regulatory module. Thus, by relieving a translational bottleneck at a single rare codon, RAS signaling coordinately elevates a diverse set of growth-promoting proteins, including RPL15, SRSF1, and CDK4, many of which are difficult to target without perturbing essential cellular functions.
How does RAS accelerate CGA decoding? Although the abundance of the cognate tRNAUCG remained unchanged in KRASG12D cells, its association with translating ribosomes increased, suggesting more efficient delivery to the ribosomal A site. This observation pointed to eEF1A, the elongation factor responsible for aminoacyl-tRNA delivery. Two complementary screens converged on METTL13, a dual methyltransferase that modified the N-terminus and K55 of eEF1A5, as the key mediator of RAS-enhanced CGA translation. Efficient CGA decoding specifically required METTL13-dependent dimethylation of eEF1A at K55, whereas N-terminal methylation was dispensable. Previous studies linked eEF1A K55 dimethylation to enhanced protein synthesis and tumorigenesis6, but Xing et al. now place this modification within a signal-responsive pathway that acts with codon specificity.
Mechanistically, the downstream MAPK effector kinase RSK phosphorylates METTL13 at S267, a residue located between its two catalytic domains. This phosphorylation stabilizes METTL13 and enhances its methyltransferase activity toward eEF1A K55. Increased K55 dimethylation, in turn, accelerates CGA decoding, likely by promoting more efficient utilization of the cognate tRNAUCG during elongation. Disrupting any step of this signaling axis — including RSK inhibition, the METTL13 S267A mutation, the eEF1A K55R substitution, or METTL13 deletion — selectively impaired CGA decoding and reduced expression of CGA-enriched proteins (Fig. 1).
The therapeutic implications are particularly compelling. In patient-derived organoids, cells exhibiting elevated CGA translation persisted after RAS pathway inhibition, resembling drug-tolerant populations. Genetic disruption of METTL13 reduced these residual cells, sensitized colorectal and pancreatic tumor organoids to RAS inhibitors, and overcame both intrinsic and acquired resistance in vivo. Reassuringly, METTL13 is expressed at relatively low levels in most normal adult tissues7, and METTL13 knockout mice are largely healthy4, suggesting that pharmacological inhibition may be well tolerated. Rather than targeting individual downstream effectors one by one, inhibiting METTL13 offers a “one-handle, multiple-effector” strategy that suppresses an entire codon-defined network of proteins involved in ribosome biogenesis, RNA splicing, and cell-cycle proteins, potentially providing more durable tumor control than approaches focused on individual resistance nodes1.
By uncovering a codon-selective translation aspect of oncogenic RAS signaling, this study also raises several important questions. First, the structural basis for CGA selectivity remains unknown. eEF1A K55 methylation may alter tRNA binding, GTPase activation, or tRNA accommodation within the ribosome, but distinguishing among these possibilities will require biochemical reconstitution and high-resolution structural analysis. Second, it remains unclear whether all CGA codons respond equally or whether local sequence context and mRNA structure modulate their sensitivity to this pathway. Notably, although CGA is the most prominent target, other arginine codons including CGC and CGU may also be influenced by this pathway. Third, similar codon-selective translational programs have begun to emerge in other oncogenic settings. For example, MYC activation or PTEN loss has been associated with preferential translation of CCC codons, whereas polyamine depletion in MYCN-driven neuroblastoma selectively stalls A-ending codons, particularly CCA8. These observations raise the intriguing possibility that different oncogenic pathways establish distinct “codon-decoding programs” to selectively remodel the proteome. The molecular mechanisms underlying these programs warrant future investigation.
From a clinical perspective, no selective METTL13 inhibitor has yet been developed. Clinical application of these findings will require both potent inhibitors and biomarkers — such as METTL13 S267 phosphorylation or a CGA-translation signature — to identify patients most likely to benefit from the treatment. More broadly, Xing et al. reveal that, by rewiring the “language” of translation rather than simply increasing the output, RAS-MAPK signaling reshapes the proteome to promote tumor growth and therapeutic resistance. The work therefore expands our view of translational control from regulation of initiation and elongation rates to regulation of the genetic code itself — a previously unappreciated layer of oncogenic signaling.

[1]

Singhal, A., Li, B.T. & O’Reilly, E.M. Nat. Med. 30, 969–983 (2024).

[2]

Zhao, Y.L. et al. Nature 599, 679–683 (2021).

[3]

Xue, J.Y. et al. Nature 577, 421–425 (2020).

[4]

Xing, S. et al. Vita https://doi.org/10.15302/vita.2026.07.0049 (2026).

[5]

Jakobsson, M.E. et al. Nat. Commun. 9, 3411 (2018).

[6]

Liu, S. et al. Cell 176, 491–504.e21 (2019).

[7]

Takahashi, A. et al. Sci. Rep. 1, 15 (2011).

[8]

Cherkaoui, S. et al. Nature 646, 707–715 (2025).

RIGHTS & PERMISSIONS

The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Cite this article

Download citation ▾
He, R., Qian, S.  A codon-specific decoding program by oncogenic RAS signaling  Vita https://doi.org/10.15302/vita.2026.07.0052 ()
AI Summary AI Mindmap
PDF (1410KB)
Sections
Figures
References

421

Accesses

0

Citation

Detail

Recommended

AI思维导图

/

〈 〉