Biology subjects

Passarelli, M. C.

Publications and source records attributed to Passarelli, M. C..

3 recordsLinked to original sources

bioRxiv2021

Two Isoleucyl tRNAs that Decode 'Synonymous' Codons Divergently Regulate Breast Cancer Progression

The human genome contains 61 codons that encode for the 20 amino acids. The synonymous codons of a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons are modulated in opposing directions during breast cancer progression. Specifically, tRNAIleUAU is upregulated, whereas tRNAIleGAU is repressed as breast cancer cells attained enhanced metastatic capacity. Functional studies revealed that tRNAIleUAU promoted and tRNAIleGAU suppressed metastatic colonization. The expression of these tRNAs mediated opposing effects on codon-dependent translation of growth promoting genes. Consistent with this, multiple mitotic gene sets in the human genome are significantly enriched in the codon cognate to the growth-promoting tRNAIleUAU and significantly depleted of the codon cognate to the growth-suppressive tRNAIleGAU. Our findings uncover a specific isoacceptor tRNA pair that act in opposition--divergently regulating genes that contribute to growth and a disease phenotype. The degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts that facilitate the transition towards a growth-promoting state.

cancer biology↗

bioRxiv2018

An adaptive stress-induced tRNA depletion response mediates codon-based gene repression and growth suppression

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine tRNAGUA fragments in human cells--causing significant depletion of the precursor tRNA. Tyrosine tRNAGUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNAGUA or its translationally regulated targets USP3 and SCD repressed proliferation--revealing a dedicated tRNA-regulated growth suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small-RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.

molecular biology↗

bioRxiv2018

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

The MUSASHI family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We found that the small molecule Ro 08-2750 (Ro) directly binds to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells resulted in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrated in vivo inhibition of c-MYC and reduced disease burden in a murine AML leukemia model. Thus, we have identified a small molecule that targets MSIs oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

cancer biology↗