Biology subjects

Arur, S.

Publications and source records attributed to Arur, S..

4 recordsLinked to original sources

bioRxiv2025

A eukaryote without tRNA introns

One of the striking characteristics of eukaryotic genomes is the presence of three types of introns: spliceosomal introns, tRNA introns, and a unique intron in the XBP1 mRNA. Exceptional eukaryotic genomes that lack spliceosomal or XBP1 introns have been described. However, tRNA introns and the tRNA endonuclease that is required for their splicing are thought to be universal in eukaryotes. The introns in three tRNAs are widely conserved across Metazoa: Tyr-GUA, Ile-UAU and Leu-CAA. This study shows that some nematode species have lost the introns in Tyr-GUA and Ile-UAU tRNAs, and one species, Levipalatum texanum, completely lacks tRNA introns. The loss of the intron from Leu-CAA tRNA is accompanied by an unusual A-C mismatched basepair in the anticodon stem loop and a triplication of a tRNA deaminase that could potentially restore basepairing. These changes may be an adaptation to the loss of the intron. L. texanum also lacks the tRNA endonuclease, one of two enzymes required for tRNA splicing. The other key enzyme in tRNA splicing, tRNA ligase, is bifunctional and is also required for XBP1 mRNA splicing. L. texanum retains tRNA ligase and the XBP1 intron. This eukaryote without tRNA introns has the potential to be a valuable tool for disentangling the functions of tRNA splicing, XBP1 splicing and tRNA modification enzymes, and is the only animal known to have lost one of the three intron types. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/660180v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1a9b5fforg.highwire.dtl.DTLVardef@eb826eorg.highwire.dtl.DTLVardef@1c03a99org.highwire.dtl.DTLVardef@14718d5_HPS_FORMAT_FIGEXP M_FIG C_FIG SIGNIFICANCEtRNA introns are thought to be a universal feature of eukaryotic genomes, including all animal genomes. We identified a species of roundworm, Levipalatum texanum, that completely lacks tRNA introns. L. texanum also lacks the tRNA splicing endonuclease, one of two enzymes required for the removal of introns from tRNAs. The second enzyme involved in this process, tRNA ligase, has a second function: the splicing of a single mRNA. Interestingly, this mRNA splicing reaction is conserved. L. texanum has an usual leucine tRNA and a three copies of a tRNA modifying enzyme that may compensate for the absence of the intron. These findings highlight that although complex RNA processing is a hallmark of eukaryotes, individual reactions may be absent in specific eukaryotes.

genomics↗

bioRxiv2022

ERK-dependent DICER1 phosphorylation promotes open chromatin state and lineage plasticity to mediate tumor progression

DICER1 controls micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) to regulate tumorigenesis of lung adenocarcinomas (LUADs). We discovered that DICER1 is phosphorylated by ERK and nuclear translocated and phospho-DICER1 contributes to tumorigenesis. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. We show that phospho-nuclear DICER1 associates with invasive human LUADs with oncogenic KRAS mutations and promotes late-stage tumor progression in mice with oncogenic Kras mutations. Surprisingly, phosphomimetic DICER1 regulates LUAD progression independent of miRNAs and EMT. Integrating single-cell RNA sequencing, fluorescent in situ RNA hybridization, immunofluorescence, and ATAC-sequencing, in mice, we discovered that phosphomimetic DICER1 generates an open chromatin state in the lung tumor alveolar cells leading to expression of gastrointestinal genes and altered AT2 cell identity. Strikingly, we also observe the gastric gene signature in human LUADs with phospho-DICER1 and KRAS mutations. We propose that phosphorylated nuclear DICER1 regulates chromatin remodeling leading to tumor cell reprogramming which drives lung cancer progression.

cancer biology↗

bioRxiv2021

Robust designation of meiotic crossover sites by CDK-2 through phosphorylation of the MutSγ complex

Crossover formation is essential for proper segregation of homologous chromosomes during meiosis. Here we show that C. elegans Cyclin-dependent kinase 2 (CDK-2) forms a complex with cyclin-like protein COSA-1 and supports crossover formation by promoting conversion of meiotic double-strand breaks (DSBs) into crossover-specific recombination intermediates. Further, we identify MutS{gamma} component MSH-5 as a CDK-2 phosphorylation target. MSH-5 has a disordered C-terminal tail that contains 13 potential CDK phosphosites and is required to concentrate crossover-promoting proteins at recombination sites. Phosphorylation of the MSH-5 tail appears dispensable in a wild- type background, but when MutS{gamma} activity is partially compromised, crossover formation and retention of CDK-2/COSA-1 at recombination sites are exquisitely sensitive to phosphosite loss. Our data support a model in which robustness of crossover designation reflects a positive feedback mechanism involving CDK-2-mediated phosphorylation and scaffold-like properties of the MSH-5 C-terminal tail, features that combine to promote full recruitment and activity of crossover-promoting complexes.

cell biology↗

bioRxiv2020

Drosha Regulates Oogenesis and microRNAs Germline Autonomously and Non autonomously in C. elegans

Small non-coding RNAs regulate multiple aspects of development including germ cell development. The microRNA pathway genes Dicer, Drosha and Pasha have been shown to regulate oocyte meiotic maturation in C. elegans. However, Dicer controls oocyte meiotic maturation through endo-siRNAs, rather than microRNAs. A repertoire of Drosha-dependent oocyte-expressed microRNAs were identified which regulate various aspects of oogenesis but not oocyte meiotic maturation. These data lead to the following models: (a) microRNAs function redundantly to regulate oocyte meiotic maturation, (b) Drosha and microRNAs function germline non-autonomously to regulate meiotic maturation. We investigated these models and observed that Drosha regulates oocyte meiotic maturation in a germline non-autonomous manner. Additionally, we uncovered a role for Drosha in regulating pachytene progression and oocyte development in a germline autonomous manner through miR-35 family and miR-51 respectively. Interestingly we also find that though Drosha-dependent oocyte-expressed microRNAs, miR-61 and miR-72, are sufficient to regulate pachytene progression and oocyte development respectively, they are generated in a germline non-autonomous manner. Collectively these data reveal a Drosha-dependent microRNA circuit, which coordinates oocyte development germline autonomously as well as through soma-germline communication.

developmental biology↗