Functional regulation of the apurinic/apyrimidinic endonuclease 1 by nucleophosmin: impact on tumor biology

Vascotto, Carlo; Lirussi, Lisa; Poletto, Mattia; Tiribelli, Mario; Damiani, D. Doḿınguez; Fabbro, Dora; Damante, Giuseppe; Demple, Bruce; Colombo, Emanuela; Tell, Gianluca

doi:10.1038/onc.2013.251

Cited by 55 publications

(106 citation statements)

References 61 publications

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“…Furthermore, while induction of genotoxic stress is reported to reduce the interaction of NPM1-APE1 in the nucleolus and release APE1 to the nucleoplasm, proximity ligation assays suggest that NPM1 and APE1 may in fact interact in the nucleoplasm as well as the nucleolus, with NPM1 possibly modulating APE1 activity in the nucleoplasm (Vascotto et al 2014). Thirdly, under the model outlined above, NPM1 is expected to act as a negative regulator of APE1.…”

Section: Holding Out: Ncl Sequesters Rpa Away From the Replication Anmentioning

confidence: 96%

“…However, studies have instead observed that, in vitro, NPM1 binding to APE1 enhances its AP-endonuclease activity (Vascotto et al 2009) lysates, despite no longer being sequestered in nucleoli (Vascotto et al 2014). NPM1 -/-cells also showed an increased sensitivity to BER-inducing agents such as H 2 O 2 , KBrO 3 and MMS, and carried a greater number of AP-sites compared to NPM1 +/+ cells, suggesting that NPM1 is in fact required for APE1 function in vivo (Vascotto et al 2014). Finally, an ongoing argument concerns the role of SIRT1, a lysine deacetylase, in the APE1-NPM1 regulatory axis.…”

Section: Holding Out: Ncl Sequesters Rpa Away From the Replication Anmentioning

confidence: 99%

“…Phenotypic analyses have revealed increased resistance to UV-induced DNA damage following NCL kd (Yang et al 2009) or NPM1 overexpression (Wu et al 2002a), though measurements of UV radiosensitivity following NPM1 kd/deletion have yielded conflicting results (Vascotto et al 2014;Wu et al 2002b). Separate groups have also used a biochemical assay for repair of a UV-irradiated reporter plasmid to demonstrate decreased NER activity following either overexpression of NCL (Yang et al 2009) or depletion of NPM1 (Wu et al 2002b), suggesting that these proteins may have opposing activities in NER regulation.…”

Section: Fix It or Fudge It: Alternative Responses To Uv-induced Damamentioning

confidence: 99%

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

Scott

Oeffinger

2016

Biochem. Cell Biol.

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The nucleolus represents a highly multifunctional intranuclear organelle in which, in addition to the canonical ribosome assembly, numerous processes such as transcription, DNA repair and replication, the cell cycle and apoptosis are coordinated. The nucleolus is further a key hub in the sensing of cellular stress and undergoes major structural and compositional changes in response to cellular perturbations.Numerous nucleolar proteins have been identified that, upon nucleolar stress sensing, deploy additional, non-ribosomal roles in the regulation of varied cell processes including cell cycle arrest, arrest of DNA replication, induction of DNA repair, and apoptosis, among others. The highly abundant proteins nucleophosmin (NPM1) and nucleolin (NCL) are two such factors that transit to the nucleoplasm in response to stress, and participate directly in the repair of numerous different DNA damages. This review discusses the contributions made by NCL and/or NPM1 to the different DNA repair pathways employed by mammalian cells to repair DNA insults, and examines the implications of such activities for the regulation, pathogenesis and therapeutic targeting of NPM1 and NCL.

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Section: Holding Out: Ncl Sequesters Rpa Away From the Replication Anmentioning

confidence: 96%

Section: Holding Out: Ncl Sequesters Rpa Away From the Replication Anmentioning

confidence: 99%

Section: Fix It or Fudge It: Alternative Responses To Uv-induced Damamentioning

confidence: 99%

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

Scott

Oeffinger

2016

Biochem. Cell Biol.

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“…More importantly, emerging evidences further highlight the importance of nucleolar hub proteins in human pathology. The link between NPM1 and oncogenesis, for example, is a well-established paradigm (31,52,151) and we recently demonstrated that in acute myeloid leukemia bearing NPM1 mutations, the cytoplasmic de-localization of the mutant NPM1c + leads to extensive BER impairment due to APE1 nuclear deprivation (150). This evidence denotes how the deregulation of an important nucleolar factor might impact on the overall cellular dynamics and not only on the ribosome biogenesis, supporting the view of the nucleolus as a multifunctional and versatile organelle.…”

Section: Dynamics Of Dna Repair Proteins During Genotoxic Damage: Nucmentioning

confidence: 99%

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

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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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.

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“…It also contributes to the removal of damaged bases within RNA (Poletto et al ., 2016; Vascotto et al ., 2014). …”

Section: Introductionmentioning

confidence: 99%

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cell RNA sequencing

et al. 2017

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Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer‐related pathways. Because APE1 is essential for cell viability, generation of APE1‐knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single‐cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial‐related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT‐PCR. Testing additional patient‐derived pancreatic cancer cells reveals particular genes (ITGA1,TNFAIP2,COMMD7,RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox‐specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis‐driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.

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Functional regulation of the apurinic/apyrimidinic endonuclease 1 by nucleophosmin: impact on tumor biology

Cited by 55 publications

References 61 publications

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

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

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

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cell RNA sequencing

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