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PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL

Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at the root of the acute promyelocytic leukemia (APL) pathogenesis. All-trans-retinoic acid (RA) treatment induces PML-RARα degradation, restores PML-NB...

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Autores principales: di Masi, A, Cilli, D, Berardinelli, F, Talarico, A, Pallavicini, I, Pennisi, R, Leone, S, Antoccia, A, Noguera, N I, Lo-Coco, F, Ascenzi, P, Minucci, S, Nervi, C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973339/
https://www.ncbi.nlm.nih.gov/pubmed/27468685
http://dx.doi.org/10.1038/cddis.2016.115
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author di Masi, A
Cilli, D
Berardinelli, F
Talarico, A
Pallavicini, I
Pennisi, R
Leone, S
Antoccia, A
Noguera, N I
Lo-Coco, F
Ascenzi, P
Minucci, S
Nervi, C
author_facet di Masi, A
Cilli, D
Berardinelli, F
Talarico, A
Pallavicini, I
Pennisi, R
Leone, S
Antoccia, A
Noguera, N I
Lo-Coco, F
Ascenzi, P
Minucci, S
Nervi, C
author_sort di Masi, A
collection PubMed
description Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at the root of the acute promyelocytic leukemia (APL) pathogenesis. All-trans-retinoic acid (RA) treatment induces PML-RARα degradation, restores PML-NB functions, and causes terminal cell differentiation of APL blasts. However, the precise role of the APL-associated PML-RARα oncoprotein and PML-NB integrity in the DSB response in APL leukemogenesis and tumor suppression is still lacking. Primary leukemia blasts isolated from APL patients showed high phosphorylation levels of H2AX (γ-H2AX), an initial DSBs sensor. By addressing the consequences of ionizing radiation (IR)-induced DSB response in primary APL blasts and RA-responsive and -resistant myeloid cell lines carrying endogenous or ectopically expressed PML-RARα, before and after treatment with RA, we found that the disruption of PML-NBs is associated with delayed DSB response, as revealed by the impaired kinetic of disappearance of γ-H2AX and 53BP1 foci and activation of ATM and of its substrates H2AX, NBN, and CHK2. The disruption of PML-NB integrity by PML-RARα also affects the IR-induced DSB response in a preleukemic mouse model of APL in vivo. We propose the oncoprotein-dependent PML-NB disruption and DDR impairment as relevant early events in APL tumorigenesis.
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spelling pubmed-49733392016-08-29 PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL di Masi, A Cilli, D Berardinelli, F Talarico, A Pallavicini, I Pennisi, R Leone, S Antoccia, A Noguera, N I Lo-Coco, F Ascenzi, P Minucci, S Nervi, C Cell Death Dis Original Article Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at the root of the acute promyelocytic leukemia (APL) pathogenesis. All-trans-retinoic acid (RA) treatment induces PML-RARα degradation, restores PML-NB functions, and causes terminal cell differentiation of APL blasts. However, the precise role of the APL-associated PML-RARα oncoprotein and PML-NB integrity in the DSB response in APL leukemogenesis and tumor suppression is still lacking. Primary leukemia blasts isolated from APL patients showed high phosphorylation levels of H2AX (γ-H2AX), an initial DSBs sensor. By addressing the consequences of ionizing radiation (IR)-induced DSB response in primary APL blasts and RA-responsive and -resistant myeloid cell lines carrying endogenous or ectopically expressed PML-RARα, before and after treatment with RA, we found that the disruption of PML-NBs is associated with delayed DSB response, as revealed by the impaired kinetic of disappearance of γ-H2AX and 53BP1 foci and activation of ATM and of its substrates H2AX, NBN, and CHK2. The disruption of PML-NB integrity by PML-RARα also affects the IR-induced DSB response in a preleukemic mouse model of APL in vivo. We propose the oncoprotein-dependent PML-NB disruption and DDR impairment as relevant early events in APL tumorigenesis. Nature Publishing Group 2016-07 2016-07-28 /pmc/articles/PMC4973339/ /pubmed/27468685 http://dx.doi.org/10.1038/cddis.2016.115 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
di Masi, A
Cilli, D
Berardinelli, F
Talarico, A
Pallavicini, I
Pennisi, R
Leone, S
Antoccia, A
Noguera, N I
Lo-Coco, F
Ascenzi, P
Minucci, S
Nervi, C
PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
title PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
title_full PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
title_fullStr PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
title_full_unstemmed PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
title_short PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL
title_sort pml nuclear body disruption impairs dna double-strand break sensing and repair in apl
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973339/
https://www.ncbi.nlm.nih.gov/pubmed/27468685
http://dx.doi.org/10.1038/cddis.2016.115
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