RNA-binding proteins that preferentially interact with 8-oxoG-modified RNAs: our current understanding.

Cells encounter a variety of stresses throughout their lifetimes. Oxidative stress can occur via a myriad of factors, including exposure to chemical toxins or UV light. Importantly, these stressors induce chemical changes (e.g. chemical modifications) to biomolecules, such as RNA. Commonly, guanine is oxidized to form 8-oxo-7,8-hydroxyguanine (8-oxoG) and this modification can disrupt a plethora of cellular processes including messenger RNA translation and stability. Polynucleotide phosphorylase (PNPase), heterogeneous nuclear ribonucleoprotein D (HNRPD/Auf1), poly(C)-binding protein (PCBP1/HNRNP E1), and Y-box binding protein 1 (YB-1) have been identified as four RNA-binding proteins that preferentially bind 8-oxoG-modified RNA over unmodified RNA. All four proteins are native to humans and PNPase is additionally found in bacteria. Additionally, under oxidative stress, cell survival declines in mutants that lack PNPase, Auf1, or PCBP1, suggesting they are critical to the oxidative stress response. This mini-review captures the current understanding of the PNPase, HNRPD/Auf1, PCBP1, and YB-1 proteins and the mechanism that has been outlined so far by which they recognize and interact with 8-oxoG-modified RNAs.

Characterization of epitranscriptome reader proteins experimentally and in silico: Current knowledge and future perspectives beyond the YTH domain.

To date, over 150 chemical modifications to the four canonical RNA bases have been discovered, known collectively as the epitranscriptome. Many of these modifications have been implicated in a variety of cellular processes and disease states. Additional work has been done to identify proteins known as "readers" that selectively interact with RNAs that contain specific chemical modifications. Protein interactomes with N6-methyladenosine (m6A), N1-methyladenosine (m1A), N5-methylcytosine (m5C), and 8-oxo-7,8-dihydroguanosine (8-oxoG) have been determined, mainly through experimental advances in proteomics techniques. However, relatively few proteins have been confirmed to bind directly to RNA containing these modifications. Furthermore, for many of these protein readers, the exact binding mechanisms as well as the exclusivity for recognition of modified RNA species remain elusive, leading to questions regarding their roles within different cellular processes. In the case of the YT-521B homology (YTH) family of proteins, both experimental and in silico techniques have been leveraged to provide valuable biophysical insights into the mechanisms of m6A recognition at atomic resolution. To date, the YTH family is one of the best characterized classes of readers. Here, we review current knowledge about epitranscriptome recognition of the YTH domain proteins from previously published experimental and computational studies. We additionally outline knowledge gaps for proteins beyond the well-studied human YTH domains and the current in silico techniques and resources that can enable investigation of protein interactions with modified RNA outside of the YTH-m6A context.