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

Abstract

Significance: An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. Recent Advances: After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. Critical Issues: A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. Future Directions: A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world. Antioxid. Redox Signal. 20, 621-639.

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

“…Several proteins, apparently unrelated to the pathway, have recently been discovered as novel unexpected coordinators of BER [15]. p53, for instance, has been implicated in the modulation of both APE1 and Polβ [6], whereas our laboratory discovered nucleophosmin (NPM1) as a modulator of the APE1 enzymatic activity [16].…”

“…p53, for instance, has been implicated in the modulation of both APE1 and Polβ [6], whereas our laboratory discovered nucleophosmin (NPM1) as a modulator of the APE1 enzymatic activity [16]. Additional regulation of the BER pathway is also achieved through evolutionarily acquired disordered extensions of some BER components [17,18]. These accessory proteins were proposed to be important for stabilizing large complexes, "repairsome", by providing extended interaction surface area [19].…”

“…Moreover, despite the previous consistent research into APE1 molecular mechanisms in DNA damage repair, only recently it has been hypothesized that this protein may play an unsuspected though important function in RNA metabolism impacting on the post-transcriptional control of gene expression [17,58,59]. Overall, these pioneering studies hold the promise to change the focus of scientific research from investigating the canonical roles of BER enzymes in DNA repair to the study of their function in gene regulation highlighting the BER peculiarity for eukaryotic cells.…”

“…A number of recent interactomic studies significantly contributed to open new scenarios for the comprehension of non-canonical functions of BER proteins, including understanding their unusual distribution in the nucleolar compartment [17,60,61] (Antoniali et al, submitted). The APE1-interactome network, characterized in part in our laboratory and in different literature works, actually comprises more than 100 different protein species whose functions are related to four biological pathways intimately interconnected: DNA repair, Excision Repair, RNA processing and Transcriptional Regulation (Fig.…”

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

“…Like NPM1 and NCL, APE1 is a remarkably pleiotropic protein that, in addition to possessing activity within BER, is able to independently regulate cellular redox sensing and act as a coactivator for several transcription factors (Antoniali et al 2014). Strikingly, APE1's AP-endonuclease activity has been shown to be active not only on cellular DNA but to mediate endonucleolytic cleavage of AP-containing ssRNA (Berquist et al 2008); in vivo, depletion of APE1 results in increased oxidation and AP-accumulation in ribosomal RNA and, consequently, decreased protein synthesis and cellular proliferation.…”