Literature summary for 4.2.99.18 extracted from

Roychoudhury, S.; Nath, S.; Song, H.; Hegde, M.L.; Bellot, L.J.; Mantha, A.K.; Sengupta, S.; Ray, S.; Natarajan, A.; Bhakat, K.K.
Human apurinic/apyrimidinic endonuclease (APE1) is acetylated at DNA damage sites in chromatin, and acetylation modulates its DNA repair activity (2017), Mol. Cell. Biol., 37, e00401-16 .

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Activating Compound

Activating Compound	Comment	Organism	Structure
additional information	acetylation of APE1 enhances its AP catalytic efficiency. ANd APE1 acetylation enhances its interaction with downstream BER proteins and stability on chromatin	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
ectopical expression of FLAG-tagged wild-type APE1 and mutants K27Q or H309N in HEK-293T cell with downregulated endogenous APE1	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
H309N	site-directed mutagenesis, the mutant still binds to chromatin and gets acetylated	Homo sapiens
K27Q	site-directed mutagenesis, chromatin-binding defective K27Q mutant, but the mutation of Lys27 in recombinant APE1 proteins does not affect acetylation by p300 at Lys6 in vitro	Homo sapiens
additional information	downregulation of endogenous APE1 levels in HEK293T cells using small interfering RNA (siRNA). Mutant phenotypes, overview	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
methoxyamine	treatment completely abrogates APE1 acetylation in a dose- and time-dependent manner. Methoxyamine (MX) covalently binds to AP sites to form methoxyamine-bound AP (MX-AP) sites and competitively inhibits the binding of APE1 to AP sites. These MX-AP sites are resistant to recognition and repair by APE1	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
chromatin	AcAPE1 is exclusively associated with chromatin throughout the cell cycle and remains bound to the condensed chromosomes. Immunohistochemic detection, the AcAPE1 Ab is highly specific for recognizing APE1 species acetylated at the N-terminal Lys6 residue and does not cross-react with a 50fold excess of unmodified APE1. Colocalization of AcAPE1 with histone H3 or active enhancer-specific histone marker acetylated H3K27 (H3K27Ac). Positive charges of acetylable Lys residues but not their acetylation are essential for the chromatin binding of APE1	Homo sapiens	785	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
additional information	Homo sapiens	in vivo, APE1 is acetylated (AcAPE1) after binding to the AP sites in chromatin and that AcAPE1 is exclusively present on chromatin throughout the cell cycle. Positive charges of acetylable lysine residues in the N-terminal domain of APE1 are essential for chromatin association. Acetylation-mediated neutralization of the positive charges of the lysine residues in the N-terminal domain of APE1 induces a conformational change; this in turn enhances the AP endonuclease activity of APE1. In the absence of APE1 acetylation, cells accumulate AP sites in the genome and show higher sensitivity to DNA-damaging agents. Positive charges of acetylable Lys residues but not their acetylation are essential for the chromatin binding of APE1	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P27695	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
acetylation	mammalian cells, unlike Saccharomyces cerevisiae or Escherichia coli cells, require acetylation of enzyme APE1 for the efficient repair of AP sites and base damage in the genome. APE1 acetylation is an integral part of the BER pathway for maintaining genomic integrity. AcAPE1 is acetylated at Lys6 and Lys7 residues in the N-terminal domain, and acetylation modulates the transcriptional coregulatory activity of enzyme APE1. APE1 is acetylated after binding to AP site damage in the chromatin, chromatin association is necessary for APE1 to be acetylated.Acetylation of APE1 enhances its AP endonuclease activity or catalytic efficiency. Methoxyamine treatment completely abrogates APE1 acetylation in a dose- and time-dependent manner. Acetylation induces a conformational change in APE1	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
A-549 cell	-	Homo sapiens	-
HEK-293T cell	-	Homo sapiens	-
IMR-90 cell	-	Homo sapiens	-
lung adenocarcinoma cell	-	Homo sapiens	-
lung fibroblast	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	in vivo, APE1 is acetylated (AcAPE1) after binding to the AP sites in chromatin and that AcAPE1 is exclusively present on chromatin throughout the cell cycle. Positive charges of acetylable lysine residues in the N-terminal domain of APE1 are essential for chromatin association. Acetylation-mediated neutralization of the positive charges of the lysine residues in the N-terminal domain of APE1 induces a conformational change; this in turn enhances the AP endonuclease activity of APE1. In the absence of APE1 acetylation, cells accumulate AP sites in the genome and show higher sensitivity to DNA-damaging agents. Positive charges of acetylable Lys residues but not their acetylation are essential for the chromatin binding of APE1	Homo sapiens	?	-	?

Synonyms

Synonyms	Comment	Organism
APE1	-	Homo sapiens
apurinic/apyrimidinic endonuclease	-	Homo sapiens

General Information

General Information	Comment	Organism
physiological function	Apurinic/apyrimidinic (AP) sites, the most frequently formed DNA lesions in the genome, inhibit transcription and block replication. The primary enzyme that repairs AP sites in mammalian cells is the AP endonuclease (APE1), which functions through the base excision repair (BER) pathway. Human DNA repair enzyme APE1 is a ubiquitous and multifunctional protein. It plays a central role in the repair of spontaneously generated AP sites and oxidative and alkylated DNA damage in the genome via the BER pathwayMammalian cells, unlike Saccharomyces cerevisiae or Escherichia coli cells, require acetylation of APE1 for the efficient repair of AP sites and base damage in the genome. APE1 acetylation is an integral part of the BER pathway for maintaining genomic integrity. Apart from its DNA repair function, APE1 functions as a redox activator of many transcription factors, as well as a direct transcriptional coregulator of many genes. APE1 is essential for embryonic development and for cell viability and/or proliferation in cultures. Human APE1 is unique in that it has an N-terminal disordered 42 amino acids and has both DNA repair and transcriptional regulatory activities. AcAPE1 is exclusively associated with chromatin throughout the cell cycle. Acetylation of APE1 enhances its AP catalytic efficiency, and APE1 acetylation enhances its interaction with downstream BER proteins and stability on chromatin. APE1 acetylation plays a role in cell survival and/or proliferation in response to genotoxic stress	Homo sapiens

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Release 2023.1 (January 2023)