Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Oct 1;10(19):3274-83.
doi: 10.4161/cc.10.19.17763. Epub 2011 Oct 1.

Pleiotropic functions of EAPII/TTRAP/TDP2: cancer development, chemoresistance and beyond

Chunyang Li  1 , Shi-Yong Sun, Fadlo R Khuri, Runzhao Li
Affiliations
Review

Pleiotropic functions of EAPII/TTRAP/TDP2: cancer development, chemoresistance and beyond

Chunyang Li et al. Cell Cycle. .

Abstract

EAPII (also called TTRAP, TDP2), a protein identified a decade ago, has recently been shown to function as an oncogenic factor. This protein was also proven to be the first 5'- tyrosyl-DNA phosphodiesterase. EAPII has been demonstrated to have promiscuous protein associations, broad responsiveness to various extracellular signals, and pleiotropic functions in the development of human diseases including cancer and neurodegenerative disease. Emerging data suggest that EAPII is a multi-functional protein: EAPII repairs enzyme (topoisomerase)-mediated DNA damage by removing phosphotyrosine from DNA adducts; EAPII is involved in multiple signal transduction pathways such as TNF-TNFR, TGFβ and MAPK, and EAPII is responsive to immune defense, inflammatory response, virus infection and DNA toxins (chemo or radiation therapy). This review focuses on the current understanding of EAPII biology and its potential relations to many aspects of cancer development, including chromosome instability, tumorigenesis, tumor metastasis and chemoresistance, suggesting it as a potential target for intervention in cancer and other human diseases.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic representation of EAPII protein structure. The UBA domain is indicated in red and the Exo_endo_phos domain in solid blue. Six exo_endo_phos motifs are indicated by the amino acid sequence and the starting and ending number and the functional critical residues are highlighted in red. The potential function of the motifs are: Asn hydrogen bonds of TWN to catalytic Asp of the GDXN motif; Glu of LQE coordinates Mg2+ or Mn2+; GDXN catalytic Asp and Asn hydrogen bonds to scissile phosphate in substrate; and the His of SDH paired with catalytic Asp forms a hydrogen bond to scissile phosphate. The phosphorylation sites (T88 and T92) are also indicated. All amino acid residues are indicated by a one-letter symbol.
Figure 2
Figure 2
Model of EAPII -mediated transcription modulation: (1) EAPII represses NFκB activity through regulating upstream events of the TRAF-NFκB cascade; (2) EAPII represses transactivation by ETS1 on the MMP1 promoter; and (3) EAPII represses transactivation by Smad3 on Snail1, which is a transcriptional repressor of E-cadherin, subsequently leading to de-repression of E-cadherin transcription. Green lines and arrows denote transactivation and black lines indicate transcriptional repression.
Figure 3
Figure 3
Model of EAPII-mediated signal transduction: (1) EAPII negatively modulates TNFα signaling; (2) EAPII facilitates or represses the JNK-mediated apoptosis pathway, depending on the genotype of DJ-1 protein; (3) EAPII activates MAPK-ERK signaling; and (4) EAPII negatively modulates Nodal signaling through Smad3 association.
Figure 4
Figure 4
Model of error-free DNA repair function of EAPII: Transit DNA break (cleavable complex) is re-ligated and DNA topological entanglement is resolved (A→B); Stabilizing the transit cleavable complex by TopoII poison results in enzyme-mediated double strand breaks (A→C); TDP2 removes TopoII from protein-DNA adducts and leaves a free phosphate at 5′ of DNA, which is ready for ligation (C→D) and double strand DNA break is repaired (D→B). The solid yellow ovals represent topoisomerase II , and “∼” indicates ester bond. Phosphodiester bond links nucleotide of DNA.
Figure 5
Figure 5
EAPII-related functions.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hahne JC, Okuducu AF, Sahin A, Fafeur V, Kiriakidis S, Wernert N. The transcription factor ETS-1: its role in tumour development and strategies for its inhibition. Mini Rev Med Chem. 2008;8:1095–1105. doi: 10.2174/138955708785909934. - DOI - PubMed
    1. Seth A, Watson DK. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer. 2005;41:2462–2478. - PubMed
    1. Pei H, Li C, Adereth Y, Hsu T, Watson DK, Li R. Caspase-1 is a direct target gene of ETS1 and plays a role in ETS1-induced apoptosis. Cancer Res. 2005;65:7205–7213. doi: 10.1158/0008-5472.CAN-04-3566. - DOI - PMC - PubMed
    1. Pei H, Yordy JS, Leng Q, Zhao Q, Watson DK, Li R. EAPII interacts with ETS1 and modulates its transcriptional function. Oncogene. 2003;22:2699–2709. doi: 10.1038/sj.onc.1206374. - DOI - PubMed
    1. Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, et al. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappaB activation. J Biol Chem. 2000;275:18586–18593. doi: 10.1074/jbc.M000531200. - DOI - PubMed

Publication types