Apr 5, 2020

Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity

Biomolecules
Lisa LirussiGianluca Tell

Abstract

Apurinic/apyrimidinic endonuclease 1 (APE1), the main mammalian AP-endonuclease for the resolution of DNA damages through the base excision repair (BER) pathway, acts as a multifunctional protein in different key cellular processes. The signals to ensure temporo-spatial regulation of APE1 towards a specific function are still a matter of debate. Several studies have suggested that post-translational modifications (PTMs) act as dynamic molecular mechanisms for controlling APE1 functionality. Interestingly, the N-terminal region of APE1 is a disordered portion functioning as an interface for protein binding, as an acceptor site for PTMs and as a target of proteolytic cleavage. We previously demonstrated a cytoplasmic accumulation of truncated APE1 in acute myeloid leukemia (AML) cells in association with a mutated form of nucleophosmin having aberrant cytoplasmic localization (NPM1c+). Here, we mapped the proteolytic sites of APE1 in AML cells at Lys31 and Lys32 and showed that substitution of Lys27, 31, 32 and 35 with alanine impairs proteolysis. We found that the loss of the APE1 N-terminal domain in AML cells is dependent on the proteasome, but not on granzyme A/K as described previously. The present work identified the protea...Continue Reading

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Mentioned in this Paper

Apex1 protein, mouse
Amino-Terminal Amino Acid
Post-Translational Protein Processing
Leukemia, Myelocytic, Acute
Spatial Processing
Alanine
Nucleophosmin
Granzyme K
Base Excision Repair
Proteolysis

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