Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy

Background: Chromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs). Methods: KMT...

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Autores: Campillo-Marcos, Ignacio|||0000-0002-7657-7127, Monte-Serrano, Eva|||0000-0002-0865-2244, Navarro-Carrasco, Elena|||0000-0002-1533-8210, García-González, Raúl|||0000-0003-4044-2543, Lazo, Pedro A.|||0000-0001-8997-3025
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270539
Acceso en línea:https://ddd.uab.cat/record/270539
https://dx.doi.org/urn:doi:10.3389/fcell.2021.715126
Access Level:acceso abierto
Palabra clave:Chaetocin
Tazemetostat
Ionizing radiation
Doxorubicin
DNA repair
Histone methylation
53BP1 foci
H2AX foci
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spelling Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality StrategyCampillo-Marcos, Ignacio|||0000-0002-7657-7127Monte-Serrano, Eva|||0000-0002-0865-2244Navarro-Carrasco, Elena|||0000-0002-1533-8210García-González, Raúl|||0000-0003-4044-2543Lazo, Pedro A.|||0000-0001-8997-3025ChaetocinTazemetostatIonizing radiationDoxorubicinDNA repairHistone methylation53BP1 fociH2AX fociBackground: Chromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs). Methods: KMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis. Results: Chaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation, and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death. 22021-01-0120212021-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/270539https://dx.doi.org/urn:doi:10.3389/fcell.2021.715126reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 BES-2014-067721Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2016-75744-RAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-105610RB-I00open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2705392026-06-06T12:50:31Z
dc.title.none.fl_str_mv Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
title Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
spellingShingle Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
Campillo-Marcos, Ignacio|||0000-0002-7657-7127
Chaetocin
Tazemetostat
Ionizing radiation
Doxorubicin
DNA repair
Histone methylation
53BP1 foci
H2AX foci
title_short Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
title_full Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
title_fullStr Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
title_full_unstemmed Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
title_sort Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy
dc.creator.none.fl_str_mv Campillo-Marcos, Ignacio|||0000-0002-7657-7127
Monte-Serrano, Eva|||0000-0002-0865-2244
Navarro-Carrasco, Elena|||0000-0002-1533-8210
García-González, Raúl|||0000-0003-4044-2543
Lazo, Pedro A.|||0000-0001-8997-3025
author Campillo-Marcos, Ignacio|||0000-0002-7657-7127
author_facet Campillo-Marcos, Ignacio|||0000-0002-7657-7127
Monte-Serrano, Eva|||0000-0002-0865-2244
Navarro-Carrasco, Elena|||0000-0002-1533-8210
García-González, Raúl|||0000-0003-4044-2543
Lazo, Pedro A.|||0000-0001-8997-3025
author_role author
author2 Monte-Serrano, Eva|||0000-0002-0865-2244
Navarro-Carrasco, Elena|||0000-0002-1533-8210
García-González, Raúl|||0000-0003-4044-2543
Lazo, Pedro A.|||0000-0001-8997-3025
author2_role author
author
author
author
dc.subject.none.fl_str_mv Chaetocin
Tazemetostat
Ionizing radiation
Doxorubicin
DNA repair
Histone methylation
53BP1 foci
H2AX foci
topic Chaetocin
Tazemetostat
Ionizing radiation
Doxorubicin
DNA repair
Histone methylation
53BP1 foci
H2AX foci
description Background: Chromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs). Methods: KMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis. Results: Chaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation, and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death.
publishDate 2021
dc.date.none.fl_str_mv 2
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/270539
https://dx.doi.org/urn:doi:10.3389/fcell.2021.715126
url https://ddd.uab.cat/record/270539
https://dx.doi.org/urn:doi:10.3389/fcell.2021.715126
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 BES-2014-067721
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2016-75744-R
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-105610RB-I00
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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