September 8th, 2024
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, Chen et al. identified RUVBL1/2 inhibition, which disrupts oncogenic translation, as the potential drug targets in colorectal cancer. Yun et al. underlined that small non-coding RNAs like SNORD118 and SNORD3A play a role in sustaining leukemia survival through RNA-Chromatin interactions. Becker et al. showed that centrosome clustering in megakaryocytes, controlled by the protein KIFC1, is vital for proplatelet formation.
RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m⁶A-Dependent Oncogenic Translation and Colorectal Tumorigenesis
Cancer Research, 2024
Chen, D., Ji, F., Zhou, Q., Cheung, H., Pan, Y., Lau, H.C.H., Liang, C., Yang, Z., Huang, P., Wei, Q. and Cheung, A.H.K.
Colorectal cancer (CRC) remains a major global health issue, with high rates of metastasis and recurrence affecting patient survival. Recent research highlights the role of N⁶-methyladenosine (m⁶A) RNA modifications in CRC, contributing to tumour progression and immune modulation. The m⁶A RNA binding protein YTHDF1 is often overexpressed in CRC and is linked to chemotherapeutic resistance. The authors of this study aimed to identify druggable targets in CRC with high YTHDF1 expression using CRISPR/Cas9 screening.
Using CRISPR-Cas9 screening of over 1,000 druggable genes, the researchers identified RUVBL1 and RUVBL2 as key targets. These genes were overexpressed in primary CRC samples and associated with poor prognosis. The study revealed that YTHDF1 and RUVBL1/2 form a positive feedback loop, where YTHDF1 enhances RUVBL1/2 translation, and RUVBL1/2 contribute to YTHDF1-driven oncogenic translation. Co-IP and mass spectrometry demonstrated that RUVBL1/2 interact with YTHDF1 in translation initiation complexes, which are crucial for mRNA translation. Tumour growth was found to be suppressed following RUVBL1/2 loss, which was also revealed by ribo-seq to impair YTHDF1-induced oncogenic signalling.
The findings suggest that RUVBL1/2 are promising drug targets. Targeting RUVBL1/2 in CRC could inhibit YTHDF1-driven oncogenic translation, potentially reducing tumour growth and improving therapeutic outcomes in YTHDF1-high CRC.
The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance
Leukemia, 2024
Yun, H., Zoller, J., Zhou, F., Rohde, C., Liu, Y., Blank, M.F., Göllner, S. and Müller-Tidow, C.
The mammalian genome encodes a wide range of transcripts, including regulatory non-coding RNAs (ncRNAs) that are vital for gene expression and chromatin regulation. While the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are well-documented, the role of ncRNAs in chromatin regulation within acute myeloid leukaemia (AML) is still not fully understood. This research focuses on analysing the RNA-chromatin interactome in AML cells to identify regulatory ncRNAs that may impact leukaemia progression.
Using the in-situ mapping of RNA-genome interactome (iMARGI) sequencing technique, this study examined RNA-genome interactions in MV4-11 leukaemia cells, which possess FLT3 and MLL mutations. The results showed that while many protein-coding mRNAs and lncRNAs associate with their transcription sites, numerous mRNAs and small ncRNAs, including snRNA and snoRNA, demonstrated trans-acting interactions with chromatin, suggesting chromatin specific functions. Additionally, SNORD118 and SNORD3A were shown to be functionally involved in chromatin association, crucial for leukaemia cell survival.
These insights advance our understanding of RNA-chromatin interactions in AML, particularly highlighting the importance of small ncRNAs like SNORD118 and SNORD3A in sustaining leukaemia cell growth. This study opens new potential avenues for AML treatment by identifying these molecules as possible therapeutic targets.
Cell cycle–dependent centrosome clustering precedes proplatelet formation
Science Advances, 2024
Becker, I.C., Wilkie, A.R., Nikols, E., Carminita, E., Roweth, H.G., Tilburg, J., Sciaudone, A.R., Noetzli, L.J., Fatima, F., Couldwell, G. and Ray, A.
Megakaryocytes (MKs) are large bone marrow cells responsible for producing platelets. During their development, MKs undergo endomitosis, increasing their DNA content and preparing for platelet production. This process involves significant changes, including the formation of proplatelets, long extensions that lead to circulating platelets. However, the role of cell cycle dynamics, particularly centrosome clustering, in platelet production has not been thoroughly explored. The authors of this study investigated how centrosome clustering in MKs influences proplatelet formation and platelet production.
The authors are the first to report centrosome clustering in hematopoietic cells, revealing it to play a critical role in proplatelet formation, likely by serving as centres for microtubule reorganization. Centrosome clustering was found to be cell cycle dependent, with the authors showing it to exclusively occur in G1 phase of interphase both in vitro and in vivo. The authors also identified the centrosomal protein kinesin family member C1 (KIFC1) as a centrosomal motor protein that promotes clustering of centrosomes in MKs.
These findings suggest that targeting centrosome clustering could be a potential therapeutic strategy to increase platelet counts in patients with thrombocytopenia, addressing the limitations of current treatments that primarily focus on increasing MK numbers.