Abstract
26S proteasomes are known as major non-lysosomal cellular machines for coordinated and specific destruction of ubiquitinylated proteins. The proteolytic activities of proteasomes are controlled by various post-translational modifications in response to environmental cues, including DNA damage. Besides proteolysis, proteasomes also associate with RNA hydrolysis and splicing. Here, we extend the functional diversity of proteasomes by showing that they also dynamically associate with microRNAs (miRNAs) both in the nucleus and cytoplasm of cells. Moreover, DNA damage induced by an anti-cancer drug, doxorubicin, alters the repertoire of proteasome-associated miRNAs, enriching the population of miRNAs that target cell cycle checkpoint regulators and DNA repair proteins. Collectively, these data uncover yet another potential mode of action for proteasomes in the cell via their dynamic association with microRNAs.
Highlights
Proteasomes are multi-protein complexes, widely known to participate in protein degradation by ubiquitindependent and ubiquitin-independent proteolysis
We first determined the conditions of genotoxic stress that caused apoptosis in K562 cells, a promyelocytic leukemia cell line with high proteasome content
We concluded that the concentration of 4 uM of DR was sufficient to induce DNA damage-induced apoptosis in K562 cells
Summary
Proteasomes are multi-protein complexes, widely known to participate in protein degradation by ubiquitindependent and ubiquitin-independent proteolysis. The 26S proteasome consists of the 20S catalytic particle (CP) and the 19S regulator particle (RP). The 20S proteasome is a barrel-shaped structure formed of four heptameric rings: the two outer rings are made of alpha-type subunits and the two inner rings are made of beta-type subunits. Beta-subunits are responsible for proteolysis, while the main function of alpha-rings is to regulate an access of a substrate to the proteolytic chamber [1, 2]. Polyubiquitinylated substrates are recognised either by the integral ubiquitin receptors subunits, Rpn and Rpn13 [3] [4, 5], or by the proteasome-associated factors that have affinity for ubiquitins (e.g. Rad23B)
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