May 28th

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, Dong et al. (2023) report that RRP15 inhibition could disrupt β-catenin signalling and inhibit CRC proliferation and metastasis. Wu et al. (2023) investigated the role of CDK13 in mRNA translation regulation using colorectal cancer (CRC) as a model. Lastly, Yamashita et al. (2023) provided valuable insights into the functional and regulatory roles of IDRs, particularly PrLDs, in stress responses and gene expression modulation.

RRP15 deficiency induces ribosome stress to inhibit colorectal cancer proliferation and metastasis via LZTS2-mediated β-catenin suppression

Cell Death & Disease, 2023
Dong, Z., Li, J., Dai, W., Yu, D., Zhao, Y., Liu, S., Li, X., Zhang, Z., Zhang, R., Liang, X. and Kong, Q. et al.

Colorectal cancer (CRC) is a significant malignancy with poor outcomes, necessitating the identification of effective biomarkers and therapeutic targets. Abnormal Wnt signalling, driven by APC mutations, promotes CRC by releasing β-catenin, which regulates genes involved in proliferation, metastasis, and drug resistance. Ribosome biogenesis protein RRP15 contributes to CRC progression by controlling protein synthesis and cell cycle. In this study, the researchers aimed to investigate the role of RRP15 in CRC progression.

The researchers investigated the impact of RRP15 knockdown on the translation of LZTS2 mRNA in colorectal cancer (CRC) cells. They hypothesized that RRP15 deficiency-induced ribosome stress might upregulate the translation of LZTS2. To test this hypothesis, they purified polysomes from RRP15 KD cells and control cells and analyzed the distribution of LZTS2 mRNA on polysome gradients. The results showed that RRP15 KD impaired ribosome biogenesis in CRC cells. Importantly, they observed a significant increase in the amount of LZTS2 mRNA on polysome gradients in RRP15 knockdown cells compared to control cells. This finding, along with the enhanced translation of another known TOP mRNA, RPL11, suggested that RRP15 deficiency stimulates the translation of LZTS2, which negatively regulates the Wnt/β-catenin signaling pathway to inhibit CRC progression.

The findings from these studies suggest that RRP15 could serve as a predictive marker and a potential therapeutic target for CRC, as its inhibition could disrupt β-catenin signalling and inhibit CRC proliferation and metastasis. .

CDK13 phosphorylates the translation machinery and promotes tumorigenic protein synthesis

Oncogene, 2023
Wu, C., Xie, T., Guo, Y., Wang, D., Qiu, M., Han, R., Qing, G., Liang, K. and Liu, H. et al.

The family of cyclin-dependent kinases (CDKs) consists of two main subclasses: cell cycle-associated CDKs and transcription-associated CDKs. CDKs play crucial roles in regulating cell cycle progression and transcriptional processes. Various CDKs have been implicated in human cancers, and CDK inhibitors are used to treat certain types of cancer. Cyclin-dependent kinase 13 (CDK13) is involved in regulating transcription. CDK13 has been found to be selectively important in various tumor contexts, suggesting its oncogenic role in tumorigenesis and disease progression. The precise mechanisms underlying CDK13’s oncogenic function remain unclear but are likely to involve alternative mechanisms. In this study, the researchers investigated the role of CDK13 in mRNA translation regulation using colorectal cancer (CRC) as a model.

Polysome profiling was used in this study to investigate the influence of CDK13 on mRNA translation and protein synthesis. Colorectal cancer cells with CDK13 knockdown were subjected to polysome profiling, where puromycin treatment and sucrose density gradient centrifugation were employed to isolate polysomes. Results showed a significant decrease in the association of MYC mRNA with polysomes in CDK13 knockdown cells, indicating impaired translation and reduced MYC protein levels. Further experiments revealed that CDK13 directly phosphorylates 4E-BP1 and eIF4B, crucial regulators of cap-dependent translation initiation. Combination treatment of CDK13 knockdown and rapamycin led to further reduction in phosphorylation, decreased MYC mRNA translation, and induced apoptotic cell death in colorectal cancer cells.

This study highlights the important role of CDK13 in promoting protein synthesis and suggests that targeting CDK13, particularly in combination with rapamycin, could be a potential therapeutic strategy for treating colorectal cancer.

ILF3 prion-like domain regulates gene expression and fear memory under chronic stress

iScience, 2023
Yamashita, A., Shichino, Y., Fujii, K., Koshidaka, Y., Adachi, M., Sasagawa, E., Mito, M., Nakagawa, S., Iwasaki, S., Takao, K. and Shiina, N.

Intrinsically disordered regions (IDRs) lack stable structures and act as interaction hubs in biomolecular complexes. The prion-like domain (PrLD), a type of IDR, is linked to neurodegenerative diseases. IDRs vary in length and may play a role in environmental responses and phenotypic diversity. While the pathological aspects of PrLDs in vertebrates are well-known, their physiological relevance remains unclear. Interleukin enhancer-binding factor 3 (Ilf3) is a gene found in vertebrates and plays a role in stress responses. The gene Ilf3 produces two transcript variants, NFAR1 and NFAR2, which regulate gene expression. NFAR1 and NFAR2 have different subcellular localizations, with NFAR2 being more nuclear-enriched due to its PrLD. NFAR2 localizes to RNP condensates in the cytoplasm. Investigating the functional implications of the PrLD requires further study using NFARs mutants.

To address this, Ilf3 mutant mice were generated by deleting the PrLD in NFAR2 (Ilf3PrLD/DPrLD mice). Chronic stress was applied to these mice for increasing oxidative stress levels in the brain. The results of the ribosome profiling analysis in the study revealed that deleting the PrLD in NFAR2 led to significant alterations in mRNA translation patterns under chronic stress conditions. The deletion of the PrLD resulted in distinct translation profiles compared to the wild-type, implicating the PrLD in modulating translation processes in response to stress. Furthermore, microscopic analysis and behavioral tests revealed that the PrLD of NFAR2 mediates nuclear retention and enhances conditioned fear memory formation in a chronic stress environment. These findings suggest that the PrLD confers versatility to respond to the environment by modulating subcellular localization rather than forming condensates.

Overall, this study provides valuable insights into the functional and regulatory roles of IDRs, particularly PrLDs, in stress responses and gene expression modulation.

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Oscar Ting

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