Stress Granule-Mediated Oxidized RNA Decay in P-Body: Hypothetical Role of ADAR1, Tudor-SN, and STAU1

Abstract

Reactive oxygen species (ROS) generated under oxidative stress (OS) cause oxidative damage to RNA. Recent studies have suggested a role for oxidized RNA in several human disorders. Under the conditions of oxidative stress, mRNAs released from polysome dissociation accumulate and initiate stress granule (SG) assembly. SGs are highly enriched in mRNAs, containing inverted repeat (IR) Alus in 3' UTRs, AU-rich elements, and RNA-binding proteins. SGs and processing bodies (P-bodies) transiently interact through a docking mechanism to allow the exchange of RNA species. However, the types of RNA species exchanged, and the mechanisms and outcomes of exchange are still unknown. Specialized RNA-binding proteins, including adenosine deaminase acting on RNA (ADAR1-p150), with an affinity toward inverted repeat Alus, and Tudor staphylococcal nuclease (Tudor-SN) are specifically recruited to SGs under OS along with an RNA transport protein, Staufen1 (STAU1), but their precise biochemical roles in SGs and SG/P-body docking are uncertain. Here, we critically review relevant literature and propose a hypothetical mechanism for the processing and decay of oxidized-RNA in SGs/P-bodies, as well as the role of ADAR1-p150, Tudor-SN, and STAU1.

Keywords: 3′ UTR; ADAR1; P-bodies; STAU1; Tudor-SN; oxidative stress; oxidized RNA; stress granules.

FIGURE 1

Hypothetical role of ADAR1, Tudor-SN, and STAU1 in stress granule-mediated oxidized RNA decay. (A) ROS-mediated oxidation of mRNA molecules and stress granule formation under oxidative stress in the cytosol. Polysome-dissociated mRNA molecules with long 3′ UTRs along with several protein factors accumulate and form membrane-free stress granules. (B) Specific recruitment of protein factors ADAR1, Tudor-SN, and STAU1 to stress granules. Under oxidative stress, ADAR1 and Tudor-SN translocate to stress granules specifically, along with STAU1. ADAR1 may preferentially hyperedit (A– I) in ds 3′ UTR regions, and Tudor-SN cleaves mRNA at IU/oxidative lesion-rich regions to produce mRNA with short 3′ UTRs. These shortened mRNAs devoid of a poly-A tail are bound by STAU1 for subsequent processing. (C) Differential routing of oxidized and unoxidized mRNA from SG. Under oxidative stress, stress granules and P-bodies physically interact. During this docking process, STAU1 in SG binds to Tudor-SN processed, oxidized mRNA and transports it to P-bodies for degradation. Additionally, upon removal of oxidative stress, unoxidized and sequestered mRNA may be released from the stress granules for translational reinitiation.