Intrusion of a DNA Repair Protein in the RNome World: Is This the Beginning of a New Era?

Abstract

3Apurinic/apyrimidinic endonuclease 1 (APE1), an essential protein in mammals, is known to be involved in base excision DNA repair, acting as the major abasic endonuclease; the protein also functions as a redox coactivator of several transcription factors that regulate gene expression. Recent findings highlight a novel role for APE1 in RNA metabolism. The new findings are as follows: (i) APE1 interacts with rRNA and ribosome processing protein NPM1 within the nucleolus; (ii) APE1 interacts with proteins involved in ribosome assembly (i.e., RLA0, RSSA) and RNA maturation (i.e., PRP19, MEP50) within the cytoplasm; (iii) APE1 cleaves abasic RNA; and (iv) APE1 cleaves a specific coding region of c-myc mRNA in vitro and influences c-myc mRNA level and half-life in cells. Such findings on the role of APE1 in the posttranscriptional control of gene expression could explain its ability to influence diverse biological processes and its relocalization to cytoplasmic compartments in some tissues and tumors. In addition, we propose that APE1 serves as a "cleansing" factor for oxidatively damaged abasic RNA, establishing a novel connection between DNA and RNA surveillance mechanisms. In this review, we introduce questions and speculations concerning the role of APE1 in RNA metabolism and discuss the implications of these findings in a broader evolutionary context.There is an emerging body of evidence that links DNA repair proteins to specific aspects of RNA metabolism. Currently, little is known about how cells cope with damaged RNA, either modified or oxidized, but it is clear that such RNA can impair protein synthesis, thus affecting cell function and viability. Specific surveillance mechanisms are therefore needed to remove damaged molecules from the RNA pool to guarantee the biological integrity of cells.The idea that quality control mechanisms might exist to repair RNA was brought to the forefront with the identification of the biochemical activities of the mammalian AlkB homologs. In particular, it was discovered that AlkB (from Escherichia coli) and the human homolog hABH3, besides being able to directly reverse alkylation damage on DNA bases, are able to demethylate damaged bases on RNA, thus playing a key role in the repair of specific RNA lesions (1, 30). While repair mechanisms have been demonstrated for alkylated RNA, such activity is not yet known for oxidatively damaged RNA. However, their existence seems improbable, in the absence of direct reversal strategies, due to the lack of a template for accurate repair, as in the case of double-stranded DNA. Since, under oxidative stress conditions, oxidation of RNA can occur up to a 10-to 20-fold-higher extent than oxidation of DNA (24), the question is: how is oxidized RNA specifically removed or repaired?The recent findings of Berquist et al. (7), Barnes et al. (4), and Vascotto et al. (39) highlight a novel "moonlighting" role for the repair apurinic/apyrimidinic (AP) endonuclease 1 (APE1) in RNA metabolism, both as a possible "cleansing" factor for damaged abasic ...

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

“…APE1 is a multifunctional and essential factor in mammals that was identified about 20 years ago as the major AP-endonuclease in the BER pathway, as well as a redox coactivator of transcription factors (37,157). The recent observation that APE1 is able to bind and cleave RNA highlighted previously unsuspected roles for the protein (77,138). We found indeed that this protein associates with NPM1 in the nucleolus, where it may have a functional role as RNA cleansing factor.…”

“…Remarkably, this peculiar region also accounts for noncanonical activities that have been ascribed to APE1, including its role in RNA metabolism (42,89,116,138,148,149). Over the past two decades, knowledge of the biological functions, mechanisms of action, interactions, and regulation of the APE1 protein has increased exponentially.…”

“…Not only 8-hydroxyguanosine (8-OHG) but also 5-hydroxycytidine, 5-hydroxyuridine, and 8-hydroxyadenosine have been identified in oxidized RNA (160). While oxidative damage to DNA is essentially repaired through the base excision repair (BER) pathway, no evidences of similar repair processes have been described for RNA molecules, even though some BER proteins recently entered the arena of the RNome world (138). If not repaired, damage to RNA molecules may lead to ribosomal dysfunctions and erroneous translation; thus, significantly affecting the overall protein synthesis mechanism (38,135).…”

“…Therefore, all the hypotheses concerning the involvement of APE1 in the development of such pathologies should be re-interpreted in light of these findings. The role played by APE1 in RNA-related processes needs further investigations, since its ability to recognize and cleave the RNA abasic sites (12,42,89,138,149) is compatible with a leading role in the early stages of the RNA quality control process. Additional studies aiming at the understanding the mechanisms related to oxidative RNA damage processing and their consequences may provide significant insights into the pathogenesis of neurodegenerative disorders, leading to improvements in the current therapeutic strategies.…”

Investigating the Cellular Localization of APE1.

“…The aforementioned findings demonstrated that APEl can recognize and cleave abasic RNA, affect cell growth through its involvement in rRNA control mechanism, play a role as a novel RNA cleansing enzyme, and affect gene expression through post-transcriptional mechanisms (Vascotto et al 2009 andTell et al 2010).…”