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Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment

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Abstract

The apurinic endonuclease 1/redox factor-1 (APE1) has a crucial function in DNA repair and in redox signaling in mammals, and recent studies identify it as an excellent target for sensitizing tumor cells to chemotherapy. APE1 is an essential enzyme in the base excision repair pathway of DNA lesions caused by oxidation and alkylation. As importantly, APE1 also functions as a redox agent maintaining transcription factors involved in cancer promotion and progression in an active reduced state. Very recently, a new unsuspected function of APE1 in RNA metabolism was discovered, opening new perspectives for this multifunctional protein. These observations underline the necessity to understand the molecular mechanisms responsible for fine-tuning its different biological functions. This survey intends to give an overview of the multifunctional roles of APE1 and their regulation in the context of considering this protein a promising tool for anticancer therapy.

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Abbreviations

8-OHG:

8-Hydroxyguanine

AP:

Apurinic/apyrimidinic

AP-1:

Activating Protein-1

APE1:

Apurinic apyrimidinic endonuclease 1

BER:

Base excision repair

CKI and CKII:

Casein kinase I and II

CREB:

cAMP-responsible element binding protein

Egr-1:

Early growth response protein-1

FEN1:

Flap endonuclease I

GSK3:

Glycogen synthase kinase 3

GzmA:

Granzyme A

GzmK:

Granzyme K

HIF-1α:

Hypoxia inducible factor-1α

MTS:

Mitochondrial targeting sequence

MPG:

Methylpurine DNA glycosylase

MYH:

Human MutY glycosylase homolog

NF-κB:

Nuclear factor-kappaB

nCaRE:

Negative calcium responsive elements

NLS:

Nuclear localization signal

NPM1:

Nucleophosmin 1

OGG-1:

8-Oxoguanine DNA glycosylase

PARP-1:

Poly(ADP-ribose) polymerase

Pax:

Paired box-containing proteins

PCNA:

Proliferating cell nuclear antigen

PEBP-2:

Polyoma virus enhancer-binding protein-2

PKC:

Protein kinase C

Polβ:

Polymerase β

PTEN:

Phosphatase and tensin homolog

PTH:

Parathyroid hormone

PTM:

Post-translational modification

RFC:

Replication factor C

ROS:

Reactive oxygen species

Trx:

Thioredoxin

XRCC1:

X-ray cross-species complementing 1

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Acknowledgments

We thank Dr. Mark R. Kelley for helpful discussions. This work was supported by grants from: MIUR (FIRB RBRN07BMCT_008 and PRIN 2008CCPKRP_003) and from MAE (Joint Mobility Projects Program 2008–2010) to G.T.

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Tell, G., Fantini, D. & Quadrifoglio, F. Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment. Cell. Mol. Life Sci. 67, 3589–3608 (2010). https://doi.org/10.1007/s00018-010-0486-4

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