Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lirussi, Lisa, Antoniali, Giulia, Scognamiglio, Pasqualina Liana, Marasco, Daniela, Dalla, Emiliano, D’Ambrosio, Chiara, Arena, Simona, Scaloni, Andrea, Tell, Gianluca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226146/
https://www.ncbi.nlm.nih.gov/pubmed/32244430
http://dx.doi.org/10.3390/biom10040531
_version_ 1783534222164623360
author Lirussi, Lisa
Antoniali, Giulia
Scognamiglio, Pasqualina Liana
Marasco, Daniela
Dalla, Emiliano
D’Ambrosio, Chiara
Arena, Simona
Scaloni, Andrea
Tell, Gianluca
author_facet Lirussi, Lisa
Antoniali, Giulia
Scognamiglio, Pasqualina Liana
Marasco, Daniela
Dalla, Emiliano
D’Ambrosio, Chiara
Arena, Simona
Scaloni, Andrea
Tell, Gianluca
author_sort Lirussi, Lisa
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7226146
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72261462020-05-18 Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity Lirussi, Lisa Antoniali, Giulia Scognamiglio, Pasqualina Liana Marasco, Daniela Dalla, Emiliano D’Ambrosio, Chiara Arena, Simona Scaloni, Andrea Tell, Gianluca Biomolecules Article 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. MDPI 2020-03-31 /pmc/articles/PMC7226146/ /pubmed/32244430 http://dx.doi.org/10.3390/biom10040531 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lirussi, Lisa
Antoniali, Giulia
Scognamiglio, Pasqualina Liana
Marasco, Daniela
Dalla, Emiliano
D’Ambrosio, Chiara
Arena, Simona
Scaloni, Andrea
Tell, Gianluca
Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity
title Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity
title_full Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity
title_fullStr Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity
title_full_unstemmed Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity
title_short Cleavage of the APE1 N-Terminal Domain in Acute Myeloid Leukemia Cells Is Associated with Proteasomal Activity
title_sort cleavage of the ape1 n-terminal domain in acute myeloid leukemia cells is associated with proteasomal activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226146/
https://www.ncbi.nlm.nih.gov/pubmed/32244430
http://dx.doi.org/10.3390/biom10040531
work_keys_str_mv AT lirussilisa cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT antonialigiulia cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT scognamigliopasqualinaliana cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT marascodaniela cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT dallaemiliano cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT dambrosiochiara cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT arenasimona cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT scaloniandrea cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity
AT tellgianluca cleavageoftheape1nterminaldomaininacutemyeloidleukemiacellsisassociatedwithproteasomalactivity