APE1: A skilled nucleic acid surgeon

Abstract

Before a deleterious DNA lesion can be replaced with its undamaged counterpart, the lesion must first be removed from the genome. This process of removing and replacing DNA lesions is accomplished by the careful coordination of several protein factors during DNA repair. One such factor is the multifunctional enzyme human apurinic/apyrimidinic endonuclease 1 (APE1), known best for its DNA backbone cleavage activity at AP sites during base excision repair (BER). APE1 preforms AP site incision with surgical precision and skill, by sculpting the DNA to place the cleavage site in an optimal position for nucleophilic attack within its compact protein active site. APE1, however, has demonstrated broad surgical expertise, and applies its DNA cleavage activity to a wide variety of DNA and RNA substrates. Here, we discuss what is known and unknown about APE1 cleavage mechanisms, focusing on structural and mechanistic considerations. Importantly, disruptions in the biological functions associated with APE1 are linked to numerous human maladies, including cancer and neurodegenerative diseases. The continued elucidation of APE1 mechanisms is required for rational drug design towards novel and strategic ways to target its associated repair pathways.

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

“…APEX1 is a major apurinic/apyrimidic (AP) endonuclease in human cells. AP sites are pre-mutagenic lesions and this enzyme is therefore part of the DNA repair machinery [ 45 ]. Relationships between APEX1 and viral infection have been documented: inhibition of APEX1 redox activity affects Kaposi’s sarcoma-associated herpes virus [ 46 ] and its knock down inhibits HIV1 and HIV2/SIV infection [ 47 ].…”

Mitochondrial Apurinic/Apyrimidinic Endonuclease 1 enhances mtDNA repair contributing to cell proliferation and mitochondrial integrity in early stages of hepatocellular carcinoma

“…Because of its crucial role, APE1 has been described as one of the factors involved in the development of numerous cancer types, and its overexpression has been associated with poor prognosis for patients [49,50,54,55]. However, until recently, researchers mainly focused on the nuclear fraction of APE1, despite the knowledge that it also may localize in the mitochondrial compartment [20,21].…”

Mitochondrial Accumulation of Apurinic/Apyrimidinic Endonuclease 1 Protein in Early Stages of Hepatocellular Carcinoma Enhances mtDNA Repairing Rate Contributing to Cell Proliferation and Mitochondrial Functionality.

“…The APE1 protein's importance in maintaining cell homeostasis by playing a major role in the BER pathway and thereby preserving the integrity of nuclear DNA has been broadly discussed [41][42][43][44][45][46][47].…”

“…Because of its crucial role, APE1 has been described as one of the factors involved in the development of numerous cancer types, and its overexpression has been associated with poor prognosis for patients [44,45,48,49]. However, until recently, researchers mainly focused on the nuclear fraction of APE1, despite the knowledge that it also may localize in the mitochondrial compartment [19,20].…”