Intrusion of a DNA repair protein in the RNome world: is this the beginning of a new era?

Abstract

Apurinic/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.

FIG. 1.

Proposed model for APE1 in RNA metabolism. NPM1 indicates nucleophosmin 1 protein, a nucleolar protein involved in ribosome biogenesis. NPM1 binds to the APE1 N-terminal domain and thus inhibits APE1 binding to RNA through direct competition. NPM1 also binds rRNA and can mask rRNA from APE1 binding. Genotoxic stress may reduce NPM1 affinity for APE1 or decrease NPM1 binding to RNA, thus freeing APE1 to exert its cleansing function on abasic RNA (39). Similarly, other unknown proteins may regulate the RNA binding modes and functions of APE1 under particular circumstances. APE1 may also regulate mRNA stability through its sequence-specific endoribonuclease activity, as in the case of c-myc m-RNA (4). Following APE1 cleavage, the exosome complex and XRN1 exoribonuclease operate to degrade the resulting RNA fragments.