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The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathoge...

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Autores principales: Petroni, M, Sardina, F, Heil, C, Sahún-Roncero, M, Colicchia, V, Veschi, V, Albini, S, Fruci, D, Ricci, B, Soriani, A, Di Marcotullio, L, Screpanti, I, Gulino, A, Giannini, G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716299/
https://www.ncbi.nlm.nih.gov/pubmed/26068589
http://dx.doi.org/10.1038/cdd.2015.81
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author Petroni, M
Sardina, F
Heil, C
Sahún-Roncero, M
Colicchia, V
Veschi, V
Albini, S
Fruci, D
Ricci, B
Soriani, A
Di Marcotullio, L
Screpanti, I
Gulino, A
Giannini, G
author_facet Petroni, M
Sardina, F
Heil, C
Sahún-Roncero, M
Colicchia, V
Veschi, V
Albini, S
Fruci, D
Ricci, B
Soriani, A
Di Marcotullio, L
Screpanti, I
Gulino, A
Giannini, G
author_sort Petroni, M
collection PubMed
description The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.
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spelling pubmed-47162992016-01-31 The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress Petroni, M Sardina, F Heil, C Sahún-Roncero, M Colicchia, V Veschi, V Albini, S Fruci, D Ricci, B Soriani, A Di Marcotullio, L Screpanti, I Gulino, A Giannini, G Cell Death Differ Original Paper The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions. Nature Publishing Group 2016-02 2015-06-12 /pmc/articles/PMC4716299/ /pubmed/26068589 http://dx.doi.org/10.1038/cdd.2015.81 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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-nc-sa/4.0/
spellingShingle Original Paper
Petroni, M
Sardina, F
Heil, C
Sahún-Roncero, M
Colicchia, V
Veschi, V
Albini, S
Fruci, D
Ricci, B
Soriani, A
Di Marcotullio, L
Screpanti, I
Gulino, A
Giannini, G
The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
title The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
title_full The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
title_fullStr The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
title_full_unstemmed The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
title_short The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
title_sort mrn complex is transcriptionally regulated by mycn during neural cell proliferation to control replication stress
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716299/
https://www.ncbi.nlm.nih.gov/pubmed/26068589
http://dx.doi.org/10.1038/cdd.2015.81
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