APE1 and SSRP1 is overexpressed in muscle invasive bladder cancer and associated with poor survival

Song, Heyu; Zeng, Jiping; Lele, Subodh M.; LaGrange, Chad A.; Bhakat, Kishor K.

doi:10.1016/j.heliyon.2021.e06756

Cited by 12 publications

(6 citation statements)

References 25 publications

(19 reference statements)

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“…Of note, the nucleolar ATR DDR activation induced by YFP-APE1-OE in this study is under unperturbed conditions in cancer cells but not in normal cells (Figure 5 ). Considering overall APE1 up-regulation in cancer patients ( 82 , 102 , 103 ), the APE1-OE-induced ATR nDDR activation provides a new insight into a previously uncharacterized but significant mechanism of the faulty DDR activation by APE1 overexpression in nucleoli of cancer but not normal cells.…”

Section: Discussionmentioning

confidence: 99%

APE1 assembles biomolecular condensates to promote the ATR–Chk1 DNA damage response in nucleolus

Zhao

McMahon

et al. 2022

Nucleic Acids Research

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Multifunctional protein APE1/APEX1/HAP1/Ref-1 (designated as APE1) plays important roles in nuclease-mediated DNA repair and redox regulation in transcription. However, it is unclear how APE1 regulates the DNA damage response (DDR) pathways. Here we show that siRNA-mediated APE1-knockdown or APE1 inhibitor treatment attenuates the ATR–Chk1 DDR under stress conditions in multiple immortalized cell lines. Congruently, APE1 overexpression (APE1-OE) activates the ATR DDR under unperturbed conditions, which is independent of APE1 nuclease and redox functions. Structural and functional analysis reveals a direct requirement of the extreme N-terminal motif within APE1 in the assembly of distinct biomolecular condensates in vitro and DNA/RNA-independent activation of the ATR DDR. Overexpressed APE1 co-localizes with nucleolar NPM1 and assembles biomolecular condensates in nucleoli in cancer but not non-malignant cells, which recruits ATR and activator molecules TopBP1 and ETAA1. APE1 protein can directly activate ATR to phosphorylate its substrate Chk1 in in vitro kinase assays. W119R mutant of APE1 is deficient in nucleolar condensation, and is incapable of activating nucleolar ATR DDR in cells and ATR kinase in vitro. APE1-OE-induced nucleolar ATR DDR activation leads to compromised ribosomal RNA transcription and reduced cell viability. Taken together, we propose distinct mechanisms by which APE1 regulates ATR DDR pathways.

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Section: Discussionmentioning

confidence: 99%

APE1 assembles biomolecular condensates to promote the ATR–Chk1 DNA damage response in nucleolus

Zhao

McMahon

et al. 2022

Nucleic Acids Research

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confidence: 99%

“…[ [38][39][40][41][42][43][44] Breast cancer Mainly nuclear staining, with nuclear and cytosolic staining in some malignant forms. [127,128] In bladder cancer (BCa), several studies detected high expression levels of the APE1 protein in tumor tissues, compared to normal adjacent tissues, that were associated with poor outcomes [39,41,44]. APE1 overexpression was also linked to lymphovascular invasion features, as high VEGFA levels and an infiltration of CD163 + tumor-associated macrophages (TAMs) [42].…”

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confidence: 99%

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Malfatti,

Bellina,

Antoniali

et al. 2023

Cells

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APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

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“…Fine-tuning mechanisms are necessary to modulate the different functions of APE1 and it is emerging that their alterations are involved in the onset of pathological states. In particular, there is a growing amount of evidence that associates APE1 overexpression with the development of several types of cancers including lung (17), colon (80), liver (81), prostate (82), ovarian (83), and bladder cancer (84). In addition to that evidence, a recent study suggested that elevated APE1 protein levels are associated with increased genome instability, leading to cellular oncogenic transformation (18).…”

Section: Discussionmentioning

confidence: 99%

Nucleolar accumulation of APE1 through condensates is mediated by rRNA forming G-quadruplex structures

Dall’Agnese,

Hannett,

Overholt

et al. 2024

Preprint

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APE1 (apurinic/apyrimidinic endodeoxyribonuclease 1) is the main endonuclease of the base excision repair (BER) pathway acting on abasic (AP)-sites in damaged DNA. APE1 is an abundant nuclear protein with a higher concentration than other BER pathway enzymes, and therefore, improper expression and localization of this factor could lead to the accumulation of toxic DNA intermediates. Altered APE1 sub-cellular localization, expression levels, or hyper-acetylation are associated with cancer development suggesting the importance of a fine-tuning mechanism for APE1 nuclear-associated processes. Recent work highlighted multi-functional roles of APE1, including rRNA quality control. However, how rRNA influences the sub-cellular localization and activity of APE1 remains poorly understood, but previously underappreciated APE1-RNA interactions may influence the ability of this protein to form biomolecular condensates and tune APE1 partitioning into nucleoli. Since nucleolar accumulation of ectopic proteins could be the result of overexpression strategies, it is imperative to have cellular models to study APE1 trafficking under physiological conditions. Here we created the first cell line to express fluorescently tagged APE1 at its endogenous locus, enabling live-cell imaging. Live-cell imaging demonstrates that APE1 nucleolar accumulation requires active rRNA transcription. When modeled in vitro, APE1 condensate formation depends on RNA G-quadruplex (rG4) structures in rRNA and is modulated by critical lysine residues of APE1. This study sheds light on the mechanisms underlying APE1 trafficking to the nucleolus and formation of RNA-dependent APE1 nucleolar condensates that may modulate a switch between the activity of this factor in rRNA processing and DNA damage repair

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APE1 and SSRP1 is overexpressed in muscle invasive bladder cancer and associated with poor survival

Cited by 12 publications

References 25 publications

APE1 assembles biomolecular condensates to promote the ATR–Chk1 DNA damage response in nucleolus

APE1 assembles biomolecular condensates to promote the ATR–Chk1 DNA damage response in nucleolus

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Nucleolar accumulation of APE1 through condensates is mediated by rRNA forming G-quadruplex structures

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