Human AP Endonuclease 1: A Potential Marker for the Prediction of Environmental Carcinogenesis Risk

Abstract

Human apurinic/apyrimidinic endonuclease 1 (APE1) functions mainly in DNA repair as an enzyme removing AP sites and in redox signaling as a coactivator of various transcription factors. Based on these multifunctions of APE1 within cells, numerous studies have reported that the alteration of APE1 could be a crucial factor in development of human diseases such as cancer and neurodegeneration. In fact, the study on the combination of an individual's genetic make-up with environmental factors (gene-environment interaction) is of great importance to understand the development of diseases, especially lethal diseases including cancer. Recent reports have suggested that the human carcinogenic risk following exposure to environmental toxicants is affected by APE1 alterations in terms of gene-environment interactions. In this review, we initially outline the critical APE1 functions in the various intracellular mechanisms including DNA repair and redox regulation and its roles in human diseases. Several findings demonstrate that the change in expression and activity as well as genetic variability of APE1 caused by environmental chemical (e.g., heavy metals and cigarette smoke) and physical carcinogens (ultraviolet and ionizing radiation) is likely associated with various cancers. These enable us to ultimately suggest APE1 as a vital marker for the prediction of environmental carcinogenesis risk.

Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction

“…The family of glycosylases involved in mitochondrial BER consists of several members: OGG1 that is able to remove the most common and the most mutagenic modification introduced to the mtDNA—8-oxo-dG [ 147 ]; UNG1, which is responsible for the removal of uracil, resulting from the spontaneous deamination of the cytosine [ 148 ]; NTH1-dichotomous enzyme, possessing glycosylase and AP lyase activities, that excises pyrimidine lesions (ThyGly, FapyG and FapyA) [ 149 ]; NEIL1 and NEIL2 that are also involved in the removal of FapyG and FapyA [ 150 ]; MYH, enzyme that detects adenine placed opposite to 8-oxo-dG [ 151 ]. After specific glycosylases have identified and extracted the damaged base, the abasic sites are resolved by APE endonuclease that prepares the DNA molecule for the Polγ mediated repair process by cleaving 3′-hydroxyl and 5′-deoxyribose-5-phosphate sites [ 152 ]. Afterwards, the newly synthesized section of DNA is ligated to the rest of the molecule by DNA ligase III.…”

Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair

“…Whenever a toxic modification on a specific nucleobase appears or leads to formation of abasic sites, base excision repair (BER) is activated to resolve this problem [16] . Key players of the BER are DNA glycosylases (uracil-DNA glycosylase (UNG) [17] , 8-oxoguanine DNA glycosylase (OGG1) [18] , n th endonuclease III-like 1 (NTHL1) [19] and nei endonuclease VIII-like 1, 2 or 3 (NEIL1/NEIL2/NEIL3) [20] ), all of which recognize different base modifications; DNA endonucleases such as apurinic/apyrimidinic endonuclease 1 (APE1) [21] ; DNA polymerases (Polβ) and DNA ligases (Lig1) [22] . Specificity of this repair pathway is achieved by activity of the glycosylases that scan DNA molecules by slightly pulling the nucleotide strain.…”

Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest‐Old Population

“…Many studies have also reported that the decline of major components (pol β , pol γ , APE1, and Sirt6) of BER pathway is associated with aging [ 84 – 89 ]. Interestingly, deficiency of APE1, a vital element of BER initiation, leads to telomere dysfunction and segregation, suggesting that BER plays a role in aging through telomere protection [ 90 , 91 ].…”