Recent Publications Harnessing the Power of Translatomics

Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.

In this week’s Sunday papers,

  • Lareau, C.A et al. find that synonymous mitochondrial DNA (mtDNA) mutations can be subject to purifying selection in a cell type–specific manner.
  • Wang, W. et al. show that eIF2B is essential for maintaining oocyte survival and early follicle development.
  • Mohanan, G. et al. demonstrate that Scd6, an RNA-binding protein, acts as a key translational regulator during genotoxic stress, linking mRNA control to the DNA damage response.

Cell type–specific purifying selection of synonymous mitochondrial DNA variation

Proceedings of the National Academy of Sciences, 2025

Lareau, C.A., Maschmeyer, P., Yin, Y., Gutierrez, J.C., Dhindsa, R.S., Gribling-Burrer, A.S., Zielinski, S., Hsieh, Y.H., Nitsch, L., Dimitrova, V., Nalbant, B., Buquicchio, F.A., Abay, T., Stickels, R.R., Ulirsch, J.C., Yan, P., Wang, F., Miao, Z., Sandor, K., Daniel, B., Liu, V., Mendez, P.L., Knaus, P., Meyer, M., Greenleaf, W.J., Kundaje, A., Smyth, R.P., Munschauer, M., Ludwig, L.S. and Satpathy, A.T.

Sunday Paper 1

The paper demonstrates that synonymous mitochondrial DNA (mtDNA) mutations—traditionally considered neutral—can be subject to purifying selection in a cell type–specific manner. Using single-cell genomics, the authors identify a synonymous variant (m.7076A>G in MT-CO1) that shows selective depletion in CD8⁺ effector memory T cells, indicating reduced cellular fitness. Using mitochondrial ribosome profiling the authors demonstrated the functional impact of the synonymous m.7076A>G mutation on mitochondrial translation. It revealed that the mutant allele is enriched in ribosome-bound fractions, indicating translational stalling rather than efficient elongation. Mechanistically, the mutation alters codon–anticodon pairing, shifting from optimal Watson–Crick–Franklin pairing to wobble-dependent decoding. This leads to mitochondrial ribosome stalling and impaired translation efficiency, despite unchanged mRNA levels. Consequently, affected cells exhibit altered clonal expansion and functional states, particularly in metabolically demanding immune subsets. The study further shows that codon syntax and tRNA availability in mitochondria are key constraints, since mitochondrial translation relies solely on a limited set of mtDNA-encoded tRNAs. Broader analyses suggest that synonymous mutations influencing codon–anticodon affinity can impact mitochondrial function across tissues, although their effects are context dependent. Overall, the work reveals that synonymous mtDNA variation is not universally neutral but can influence translation and cell fitness, uncovering a previously underappreciated layer of functional genetic variation shaped by cell type–specific purifying selection.

Learn more about EIRNABio’s ribosome profiling services here.

Oocyte-specific knockout of eIF2B subunits causes apoptosis of mouse oocytes within the early growing follicles via DNA damage and mitochondrial dysfunction

Cell Death & Disease, 2026

Wang, W., Liu, H., Li, B., Liu, S., Zhang, L., Wei, Y., Wei, H., Zhang, X., Hao, X. and Zhang, M.

Sunday Paper 2

The study shows that eIF2B is essential for maintaining oocyte survival and early follicle development. Oocyte-specific knockout of eIF2B subunits (Eif2b2, Eif2b3, Eif2b4, and Eif2b5, but not Eif2b1) leads to apoptosis of oocytes in early growing follicles, resulting in impaired folliculogenesis and female infertility. Ribosome profiling (Ribo-seq) in this study provides critical insight into how loss of eIF2B disrupts translational control in oocytes. Puromycin incorporation showed that Eif2b4 depletion reduces global protein synthesis, while integrated Ribo-seq and RNA-seq revealed selective changes in the translation of stress, DNA damage, and oocyte development related genes. This reveals activation of the integrated stress response (ISR) at both transcriptional and translational levels. Importantly, Ribo-seq uncovers that impaired translation is not uniform but targets key pathways governing mitochondrial function and oocyte development, thereby linking defective protein synthesis directly to apoptosis and follicle dysfunction in premature ovarian insufficiency. The knockout also induces mitochondrial dysfunction, evidenced by reduced mitochondrial membrane potential, decreased mtDNA copy number and ATP production, and increased reactive oxygen species (ROS). These mitochondrial defects are linked to DNA damage accumulation and activation of the DNA damage response (DDR), including increased levels of NBS1, phosphorylated ATM/CHK2, p53 and γH2AX, alongside reduced levels of the DNA repair protein Polβ. This triggers apoptotic pathways marked by increased BAX and decreased BCL-xL. Overall, the study demonstrates that eIF2B maintains oocyte viability by supporting translation, mitochondrial function, and genome integrity, and its loss leads to apoptosis via coordinated mitochondrial dysfunction and DNA damage, providing insight into mechanisms underlying premature ovarian insufficiency.

Learn more about EIRNABio’s ribosome profiling services here.

Genotoxic stress triggers Scd6-dependent regulation of translation to modulate the DNA damage response

EMBO reports, 2025

Mohanan, G., Roy, R., Malka-Mahieu, H., Lamba, S., Fabbri, L., Kalia, S., Biswas, A., Martineau, S., M Labbé, C., Vagner, S. and Rajyaguru, P.I.

Sunday Paper 3

The study demonstrates that Scd6, an RNA-binding protein, acts as a key translational regulator during genotoxic stress, linking mRNA control to the DNA damage response. Upon exposure to DNA-damaging agents (e.g., hydroxyurea, UV, MMS), Scd6 relocalizes to cytoplasmic RNA granules, where it modulates mRNA fate rather than affecting global translation. A central finding is that Scd6 selectively represses translation of specific DNA repair mRNAs, particularly SRS2, by directly binding its transcript and sequestering it into granules. This repression occurs independently of the canonical eIF4G1-mediated mechanism and is regulated by arginine methylation and the LSm domain of Scd6, which control its RNA-binding activity. Polysome profiling in this study provides critical evidence that Scd6 regulates gene expression at the level of translation rather than transcription. The data show that Scd6 overexpression during hydroxyurea-induced stress significantly reduces SRS2 mRNA association with polysomes, indicating translational repression, while global translation remains unaffected. This selective shift confirms that Scd6 targets specific mRNAs instead of broadly inhibiting protein synthesis. The study further shows that the human ortholog LSM14A performs a conserved function, repressing translation of DNA repair proteins such as RTEL1 and LIG4, both of which have been implicated in NHEJ. Disruption of this regulation alters NHEJ activity, demonstrating that translational control can directly influence DNA repair activity. Overall, the paper reveals a previously underappreciated layer of the DNA damage response in which stress-induced, transcript-specific translational repression by RNA-binding proteins fine-tunes genome stability mechanisms.

Learn more about EIRNABio’s polysome profiling services here.