Polyubiquitination of apurinic/apyrimidinic endonuclease 1 by Parkin

Scott, Terrance M.; Wicker, Christina A.; Rangaswamy, Suganya; Dhar, Bithika; Pittman, Thomas; Horbinski, Craig; Izumi, Tohru

doi:10.1002/mc.22495

Cited by 24 publications

(14 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Growing evidence suggests that cisplatin would accumulate in and interact with various cell organelles in response to oxidative stress and unrelated or indirect DNA effects, such as reactive oxygen species (ROS) production . APE1 is an essential protein crucial for the repair of oxidized DNA damage not only in genomic DNA but also in mitochondrial DNA . In our previous work, we found that APE1 could translocalize to mitochondria after photodynamic therapy and protect cells from apoptosis .…”

Section: Discussionsupporting

confidence: 90%

Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

Liu

Zhang

et al. 2020

Cell Biochemistry & Function

View full text Add to dashboard Cite

Chemotherapy resistance has become a hold back and major clinical challenge in osteosarcoma cancer. The alteration and subcellular distribution of apurinic/ apyrimidinic endonuclease 1 (APE1) has been reported to be involved in chemotherapy resistance in many cancers. Here, we report that the cytoplasmic distribution of APE1 plays a key role in the sensitivity of combination platinum chemotherapy in osteosarcoma. Interestingly, the prevalence of cisplatin-induced DNA damage and apoptosis in low cytoplasmic APE1 osteosarcoma cell lines was higher than in high expression of cytoplasmic APE1 cell lines. Overexpression of cytoplasmic APE1 protected the osteosarcoma cells from CDDP-induced apoptosis. In addition, clinical data also show that the level of cytoplasmic APE1 was negatively associated with sensitivity to combination chemotherapy of cisplatin in osteosarcoma patients. Our findings suggest that cytoplasmic APE1 plays a significant role in chemotherapy resistance. This role is a supplement to the extranuclear function of APE1, and cytoplasmic APE1 expression level could be a promising predictor of platinum treatment prognosis for osteosarcoma patients. K E Y W O R D S APE1, cisplatin resistance, cytoplasmic, predictor 1 | INTRODUCTION Osteosarcoma has become the most common primary malignant bone tumor, mainly in adolescent and young patients. 1,2 Cisplatin is one of the traditional chemotherapeutic agents used for osteosarcoma treatment. The mechanism of toxicity cisplatin is crosslinking DNA and formed DNA-cisplatin adducts, which in turn induce DNA damage. 3 Platinum-based drugs are the standard first-line agents used alone or in combination with other drugs for osteosarcoma treatment. 4,5 However, the present protocols seem to have reached a plateau, 6 which may be associated with chemotherapy resistance. The molecular mechanisms of cisplatin resistance are complex and usually associated with a reduction in the intracellular accumulation of the platinum compounds and an increase in DNA damage repair. 3 Chemotherapy resistance has been linked with poor prognosis. Human apurinic/apyrimidinic endonuclease 1 (APE1/Ref-1) is a multifunctional protein that has both DNA damage repair and redox functions. As an essential enzyme in DNA base excision repair (BER), APE1 is involved in repairing DNA damage, creating an abasic site (apurinic/apyrimidinic, AP site) caused by oxidizers and alkylating agents. 7 APE1 is the key regulator in the cellular oxidative stress pathway, which maintains the activity of numerous cellular transcription factors, such as AP-1, NF-κB, Myb, HIF-1α, HLF, PAX, and p53, through keeping specific cysteine residues in the DNA binding domain reduced state. Moreover, some of these transcription factors are closely related to chemotherapy resistance. 8-10List of Abbreviations: AMLs, acute myeloid leukemias; Ang II, angiotensin II; AP sites, apurinic/apyrimidinic sites; AP-1, activator protein 1; APE1, apurinic/apyrimidinic endonuclease; BER, base excision repair; GADD45α, DNA damage-inducible pr...

show abstract

Section: Discussionsupporting

confidence: 90%

Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

Liu

Zhang

et al. 2020

Cell Biochemistry & Function

View full text Add to dashboard Cite

show abstract

“…Another BER member, APE1, is regulated by Parkin an E3 ubiquitin ligase, which when mutated can cause autosomal recessive early onset PD (Shimura et al, 2000). Interestingly, APE1 is ubiquitinated in a Parkin‐dependent manner and PD‐causing mutations in Parkin abrogate this ubiquitination, resulting in APE1 accumulation (Scott et al, 2017). Genetic studies further support a role for BER variants in the development of PD.…”

Section: Ber and Dna Single‐strand Damagementioning

confidence: 99%

DNA damage and repair in Parkinson's disease: Recent advances and new opportunities

Gonzalez‐Hunt

Sanders

2020

J of Neuroscience Research

View full text Add to dashboard Cite

Parkinson's disease (PD) is the most common movement neurodegenerative disorder. Although our understanding of the underlying mechanisms of pathogenesis in PD has greatly expanded, this knowledge thus far has failed to translate into disease‐modifying therapies. Therefore, it is of the utmost urgency to interrogate further the multifactorial etiology of PD. DNA repair defects cause many neurodegenerative diseases. An exciting new PD research avenue is the role that DNA damage and repair may play in neuronal death. The goal of this mini‐review was to discuss the evidence for the types of DNA damage that accumulates in PD, which has provided clues for which DNA repair pathways, such as DNA double‐strand break repair, are dysfunctional. We further highlight compelling data for activation of the DNA damage response in familial and idiopathic PD. The significance of DNA damage and repair is emerging in the PD field and linking these insights to PD pathogenesis may provide new insights into PD pathophysiology and consequently lead to new therapies.

show abstract

“…Specifically, acetylated residues (Lys27, Lys31, Lys32 and Lys35) are clustered in the protein N-terminus and are involved in protein-protein interactions [7], APE1 binding to RNAs and DNAs [35], endonuclease activity [5,15,35] and protein binding to nCaRE sequences [36]. Moreover, these residues are ubiquitinated by several ubiquitin ligases (e.g., MDM2, UBR3 and Parkin) [8,37,38], which thus control the steady state level of the protein. Additionally, APE1 enzymatic activities are controlled by interactions involving its N-terminal region [23].…”

Section: Discussionmentioning

confidence: 99%

Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity

et al. 2020

View full text Add to dashboard Cite

Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolution of DNA damages through the base excision repair (BER) pathway, acts as a multifunctional protein in different key cellular processes. The signals to ensure temporo-spatial regulation of APE1 towards a specific function are still a matter of debate. Several studies have suggested that post-translational modifications (PTMs) act as dynamic molecular mechanisms for controlling APE1 functionality. Interestingly, the N-terminal region of APE1 is a disordered portion functioning as an interface for protein binding, as an acceptor site for PTMs and as a target of proteolytic cleavage. We previously demonstrated a cytoplasmic accumulation of truncated APE1 in acute myeloid leukemia (AML) cells in association with a mutated form of nucleophosmin having aberrant cytoplasmic localization (NPM1c+). Here, we mapped the proteolytic sites of APE1 in AML cells at Lys31 and Lys32 and showed that substitution of Lys27, 31, 32 and 35 with alanine impairs proteolysis. We found that the loss of the APE1 N-terminal domain in AML cells is dependent on the proteasome, but not on granzyme A/K as described previously. The present work identified the proteasome as a contributing machinery involved in APE1 cleavage in AML cells, suggesting that acetylation can modulate this process.

show abstract

Polyubiquitination of apurinic/apyrimidinic endonuclease 1 by Parkin

Cited by 24 publications

References 80 publications

Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

DNA damage and repair in Parkinson's disease: Recent advances and new opportunities

Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity

Contact Info

Product

Resources

About