Biology subjects

Ghatpande, P.

Publications and source records attributed to Ghatpande, P..

2 recordsLinked to original sources

bioRxiv2020

Control of ribosomal protein synthesis by Microprocessor complex

Ribosome biogenesis in eukaryotes requires stoichiometric production and assembly of 80 ribosomal proteins (RPs) and 4 ribosomal RNAs, and its rate must be coordinated with cellular growth. The indispensable regulator of RP biosynthesis is the 5-terminal oligopyrimidine (TOP) motif, spanning the transcription start site of all RP genes. Here we show that the Microprocessor complex, previously linked to the first step of processing microRNAs (miRNAs), coregulates RP expression by binding the TOP motif of nascent RP mRNAs and stimulating transcription elongation via resolution of DNA/RNA hybrids. Cell growth arrest triggers nuclear export and degradation of the Microprocessor protein Drosha by the E3 ubiquitin ligase Nedd4, accumulation of DNA/RNA hybrids at RP gene loci, decreased RP synthesis, and ribosome deficiency, hence synchronizing ribosome production with cell growth. Conditional deletion of Drosha in erythroid progenitors phenocopies human ribosomopathies, in which ribosomal insufficiency leads to anemia. Outlining a miRNA-independent role of the Microprocessor complex at the interphase between cell growth and ribosome biogenesis offers a new paradigm by which cells alter their protein biosynthetic capacity and cellular metabolism.

molecular biology↗

bioRxiv2019

Tissue-specific 3 prime end-adenylation of miR-125b mediates cell survival

Next-generation sequencing has uncovered microRNAs (miRNAs) that undergo sequence modifications, known as isomiRs. Their physiological significance, however, remains uncertain, partly because they generally comprise a small fraction of total miRNAs. Here we report that more than 60% of miR-125b, one of the most abundant miRNAs in vascular smooth muscle cells (vSMC), exists as an edited isoform containing a non-templated adenosine residue at the 3 prime-end (miR-125b+A). The properties of miR-125b+A, such as stability and subcellular localization, are similar to those of canonical miR-125b, but miR-125b+A more potently inhibits the expression of a subgroup of targets, including the apoptosis effector Caspase-6 (CASP6). In the CASP6 transcript, adenylated miR125b preferentially targets a conserved, atypical site, with an unusual 36 nucleotides loop between seed sequence and 3 prime-end supplementary site. PAP associated domain containing 2 (PAPD2) is responsible for monoadenylation of miR-125b. Downregulation of PAPD2 results in the conversion of miR-125b+A to miR-125b, derepression of CASP6, and sensitization of vSMC to apoptotic stimuli. Thus, atypical site recognition by a tissue-specific isomiR fulfills a pro-survival role.

molecular biology↗