Dysregulation of tRNA: a new paradigm for cancer therapies
PI: Estaban Orellana
Assistant Professor, Molecular and Systems Biology
tRNA activity can drive pathological processes in a codon-dependent manner, but these mechanisms have never been explored in the context of cancer vulnerability. Transfer RNAs (tRNAs) can regulate protein synthesis dynamics by determining translation velocity, shaping mRNA translation profiles. Thus, regulation of tRNA metabolism is critical for cellular homeostasis, and misregulation of tRNA modification pathways is associated with human diseases. For example, the tRNA methyltransferase complex METTL1-WDR4 catalyzes the N7-methylguanosine modification of a tRNA subset and is dysregulated in human cancers. METTL1-WDR4-induced m7G tRNA methylation is essential to control tRNA folding and stability, which affects the translation of mRNAs harboring relevant cognate codons. Multiple lines of evidence show that METTL1, the catalytic subunit, functions as an oncogene through the stabilization and concomitant accumulation of tRNAs, showing that reprogramming of mRNA translation via changes in the tRNA pool can contribute to oncogenesis. For instance, the neuronal development associated tRNA isoform tRNA-Arg-TCT-4-1 possesses oncogenic characteristics and is highly elevated in multiple types of human cancer. On the other hand, failure to deposit m7G leads to the degradation of tRNAs that have been under-modified, as observed in the Rapid tRNA Decay pathway (RTD) in yeast. Despite the growing awareness of the importance of tRNA quality control in normal physiology, it is unclear whether an analogous RTD or other quality control pathways that govern tRNA function are altered in mammalian systems or cancer. Hence, the proposal goals are two-fold: 1) what are the mechanisms underlying the removal of m7G hypomodified tRNAs? and 2) Is the METTL1 substrate tRNA-Arg-TCT-4-1 a potential cancer vulnerability? Successful completion of the proposed work is expected to provide insight into the fundamental basis for understanding the role of m7G tRNA modification and its regulation in normal and malignant growth.
Understanding the Role of Meiotic Misregulation in Germ Cell Tumor Formation
PI: Soni Lacefield, PhD
Professor of Biochemistry and Cell Biology
During female reproduction, eggs are made through the process of oogenesis, which couples cellular differentiation with the specialized cell division process of meiosis. During meiosis, chromosome replication is followed by two meiotic divisions in which chromosomes segregate in each division. During meiosis I half the chromosomes are extruded into a polar body and half remain in the egg. In meiosis II, the egg arrests just prior to segregation to await fertilization. Only upon fertilization is meiosis II completed, extruding half the chromosomes into another polar body. How eggs remain in a meiosis II arrest is poorly understood, but previous studies have shown that a failure to maintain the arrest causes poor fertility and germ cell tumors. This project studies mouse oogenesis to understand the mechanisms of meiosis II regulation to determine how the egg stays in a state that is competent for fertilization. In addition, the project will determine how germ cell tumors form when eggs fail to maintain the arrest.
Understanding the role of RNA-binding protein mutations in cancer
PI: Prerna Malaney, PhD
Assistant Professor of Biochemistry and Cell Biology
The discovery of therapeutically actionable genetic lesions in malignancies has revolutionized patient care. However, many cancers lack targetable driver mutations or experience relapse after targeted therapies, leading to limited treatment options and a poor overall prognosis. We suggest that identifying non-traditional drivers of malignant transformation can unveil new therapeutic targets. To identify potential drivers, we relied on a recently published survey of the COSMIC cancer mutation database and found that approximately 5% of all mutated genes (n=65) in cancer are RNA-binding proteins (RBPs). RBPs interact with multiple target RNAs and regulate post-transcriptional processing, including splicing, poly-adenylation, degradation, and translation. The overarching goal of my research is to elucidate the role of RBPs in key cellular processes, establish the role of RBP mutations in tumorigenesis, and pinpoint therapeutic vulnerabilities in downstream signaling pathways. The culmination of these studies will strengthen the understanding of the role of RBPs in crucial biological processes and the involvement of dysregulating mutations as drivers of disease.