Biology subjects

Komur, A. A.

Publications and source records attributed to Komur, A. A..

3 recordsLinked to original sources

bioRxiv2021

An mRNA silencing mechanism reliant on the cooperation between REGE-1/Regnase-1 and RLE-1/Roquin-1

Regnase-1 is an evolutionarily conserved endoribonuclease, degrading diverse mRNAs important, among others, for immune homeostasis, development, and cancer. There are two competing models of Regnase-1 mediated mRNA silencing. One model postulates that Regnase-1 works together with another RNA-binding protein, Roquin-1. The other model proposes that the two proteins function separately. Studying the C. elegans Regnase-1 ortholog, REGE-1, we have uncovered a functional relationship between REGE-1 and the nematode counterpart of Roquin-1, RLE-1. While REGE-1 and RLE-1 associate with mRNA independently of each other, both proteins are essential for mRNA silencing. Intriguingly, the functional interdependence between REGE-1 and RLE-1 is reminiscent of the proposed cooperation between mammalian Regnase-1 and Roquin-1, which may underlie a prototypic silencing mechanism involving both proteins.

molecular biology↗

bioRxiv2021

Surviving hypothermia by ferritin-mediated iron detoxification

How animals rewire cellular programs to survive cold is a fascinating problem with potential biomedical implications, ranging from emergency medicine to space travel. Studying a hibernation-like response in the free-living nematode Caenorhabditis elegans, we uncovered a regulatory axis that enhances the natural resistance of nematodes to severe cold. This axis involves conserved transcription factors, DAF-16/FoxO and PQM-1, which jointly promote cold survival by upregulating FTN-1, a protein related to mammalian Fth1/ferritin. Moreover, we show that inducing expression of Fth1 also promotes cold survival of mammalian neurons, a cell type particularly sensitive to deterioration in hypothermia. Our findings in both animals and cells suggest that FTN-1/Fth1 facilitates cold survival by detoxifying ROS-generating iron species. We finally show that mimicking the effects of FTN-1/Fth1 with drugs protects neurons from cold-induced degeneration, opening a potential avenue to improved treatments of hypothermia.

physiology↗

bioRxiv2020

RAN translation of the expanded CAG repeats in the SCA3 disease context

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translated ATXN3 sequences with an increasing number of CAG repeats. We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating that ATXN3 sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at non-cognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. We suggest that RAN translation in SCA3 is a common event substantially contributing to SCA3 pathogenesis and that the ATXN3 sequence context plays an important role in triggering this unconventional translation.

molecular biology↗