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

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 proteasome as a contributing machinery involved in APE1 cleavage in AML cells, suggesting that acetylation can modulate this process.

• Authors: Lisa Lirussi, Giulia Antoniali, Pasqualina Liana Scognamiglio, Daniela Marasco, Emiliano Dalla, Chiara D'Ambrosio, Simona Arena, Andrea Scaloni, Gianluca Tell
• Journal: Biomolecules (Biomolecules) Vol. 10 Issue 4 (03 31 2020) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 32244430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteasome Endopeptidase Complex
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Acetylation
• Amino Acid Sequence
• Cell Line, Tumor
• DNA-(Apurinic or Apyrimidinic Site) Lyase (chemistry, metabolism)
• Humans
• Leukemia, Myeloid, Acute (pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Domains
• Proteolysis