May 12th, 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, Vrettos et al. revealed the crucial role of N-terminal arginine methylation in MIWI proteins for regulating piRNA amplification and maintaining gene stability during spermatogenesis. Wang et al. studied how estrogen receptor β (ERβ) activation in triple-negative breast cancer affects RNA splicing, leading to altered protein function and increased DNA damage. Yang et al. determined that the peptides PhD30 & PhD35, which target ZAKα-RPS20 interactions, disrupt mitochondrial function in cancer cells, paving the way for therapies that slow tumour growth without inducing apoptosis.
MIWI N-terminal arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis
Nucleic Acids Research, 2024
Nicholas Vrettos, Jan Oppelt, Ansgar Zoch, Paraskevi Sgourdou, Haruka Yoshida, Brian Song, Ryan Fink, Dónal O’Carroll and Zissimos Mourelatos
PIWI proteins, the key components of the PIWI pathway, are known to play an important role in germline epigenetic regulation. In mice, three PIWI proteins are expressed, one among which is MIWI (PIWIL1). This study focuses on the critical role of N-terminal arginine (NTR) methylation of MIWI proteins in spermatogenesis, particularly through their interaction with Tudor domain-containing proteins (TDRDs) which are pivotal in piRNA biogenesis. MIWI proteins, when methylated at their NTRs, interact with various TDRDs to facilitate the production and function of piRNAs, which are essential for transposon silencing and gene regulation during spermatogenesis.
The authors revealed that the methylation of MIWI NTRs is crucial for the interaction with TDRD5 and TDRKH, which in turn influences piRNA amplification. The loss of these interactions leads to defective piRNA amplification, rather than an outright failure of piRNA biogenesis, indicating a nuanced role of these methylations in maintaining piRNA levels necessary for effective transposon silencing and gene regulation during sperm development.
Furthermore, the study highlights that while a vast majority of pachytene piRNAs appear dispensable, a selected few are crucial for targeting specific mRNAs necessary for spermatogenesis. These findings underscore the selective pressure on MIWI protein functions mediated by NTR methylation, ensuring the propagation and stability of essential piRNAs. Additionally, MIWI’s interaction with TDRD6, facilitated by NTR methylation, is shown to be necessary for the proper compaction of the chromatoid body, a structure critical for sperm formation.
In summary, the study concludes that a central molecular mechanism by which PIWI proteins are directed and utilised by distinct cellular pathways, resides in the NTR domain.
Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triplenegative breast cancer
Proceedings of the National Academy of Sciences, 2024
Dongfang Wang, Muya Tang, Peidong Zhang, Kailin Yang, Liang Huang, Mengrui Wu, Qiuhong Shen, Jing Yue, Wei Wang, Yanqiu Gong, Margaret Warner, Lunzhi Dai, Haihuai He, Zhengnan Yang, Jan-Ake Gustafsson and Shengtao Zhou
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behaviour and poor prognosis. Novel target-based therapies for curing TNBC are being developed as potential alternatives for currently used chemotherapy. This study examines the translatomic alterations induced by estrogen receptor β (ERβ) activation in TNBC and reveals that its activation leads to substantial alterations in RNA splicing, particularly influencing the alternative splicing of the 5-oxoprolinase (OPLAH) gene, which encodes a critical enzyme involved in glutathione metabolism and oxidative stress.
The study illustrates that ERβ activation modulates the intron retention (IR) of OPLAH, which leads to subsequent DNA damage and formation of truncated proteins with impaired enzymatic function within TNBC cells. Further in-depth RNA-sequencing and ribosome profiling confirma that alternative splicing of OPLAH is influenced by splicing factor U2AF1 that interacts with ERβ.
These findings are further supported by data analysis, including samples from The Cancer Genome Atlas (TCGA). The authors demonstrate a strong correlation in the expression patterns of ESR2 (gene encoding ERβ) and U2AF1 in TNBC patients, suggesting that the observed pathway may be a prominent target for TNBC treatment.
Targeting ZAKα Interactions and Ribosomes with Novel peptides: The role of ZAKα in Mitochondrial Function and Cancer Cell Proliferation
Research Square, 2024
Dysregulation of ZAKα, a kinase that plays an important role in various cellular processes, including proliferation, differentiation, and stress response, can lead to malignant tumor growth or various heart diseases. In this paper, the authors showcase it as a potential target for inhibiting cancer cell growth by impeding mitochondrial activity.
The study highlights the use of phage display to identify two peptides, PhD30 and PhD35, that bind specifically to ZAKα. These peptides, when introduced into cancer cells, inhibit its association with ribosomal initiation complexes, including RPS20 protein. This inhibition of association with ZAKα leads to the ubiquitination of RPS20, subsequently disrupting mitochondrial translation processes and reducing mitochondrial protein levels and activity.
Further exploration revealed that the binding of PhD30 and PhD35 and subsequent impairment of mitochondrial protein translation results in decrease in crucial oxidative phosphorylation complexes, which in turn decreases the mitochondrial membrane potential and basal oxygen consumption rate, resulting in cell proliferation arrest without inducing apoptosis. This mechanism suggests a direct impact on the energy metabolism within the cancer cells, presenting PhD peptides as promising molecules for cancer therapy.