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...
Autores principales: | , , , , , , , , |
---|---|
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 |