Biology subjects

Goodarzi, H.

Publications and source records attributed to Goodarzi, H..

3 recordsLinked to original sources

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

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Post-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m6A RNA methylation machinery to its target transcripts, where deposition of m6A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression.\n\nRESEARCH HIGHLIGHTSO_LIThe RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleus\nC_LIO_LINuclear TARBP2 recruits the methyltransferase complex to deposit m6A marks on its target transcripts\nC_LIO_LITARBP2 and m6A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.\nC_LIO_LIIncreased TARBP2 expression is associated with lung cancer and promotes lung cancer growth in vivo.\nC_LIO_LIThe transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.\nC_LI

molecular biology↗

bioRxiv2018

The RNA demethylase FTO targets m6Am in snRNA to establish distinct methyl isoforms that influence splicing

Small nuclear RNAs (snRNAs) are core spliceosome components and mediate pre-mRNA splicing. During their biogenesis, snRNAs acquire several constitutive nucleotide modifications. Here we show that snRNAs also contain a regulated and reversible nucleotide modification causing them to exist as two different methyl isoforms, m1 and m2, reflecting the methylation state of the adenosine adjacent to the snRNA cap. We find that snRNA biogenesis involves the formation of an initial m1-isoform with a single-methylated adenosine (2-O-methyladenosine, Am), which is then converted to a dimethylated m2-isoform (N6,2-O-dimethyladenosine, m6Am). The relative m1- and m2-isoform levels are determined by the RNA demethylase FTO, which selectively demethylates the m2-isoform. We show FTO is inhibited by endogenous metabolites, resulting in increased m2-snRNA levels. Furthermore, cells that exhibit high m2-snRNA levels show altered patterns of alternative splicing. Together, these data reveal that FTO has a central role in snRNA biogenesis and controls a previously unknown step of snRNA processing involving reversible methylation, thereby providing a potential link between reversible RNA modifications and mRNA splicing.

molecular biology↗