DNA damage signalling histone H2AX is required for tumour growth

Cancer most frequently develops in self-renewal tissues that are the target of genetic alterations due to mutagens or intrinsic DNA replication errors. Histone γH2AX has a critical role in the cellular DNA repair pathway cascade and contributes to genomic stability. However, the role of γH2AX in the...

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Autores: Contreras Lara, Lizbeth Araceli, García Gaipo, Lorena|||0000-0002-5998-0344, Casar Martínez, Berta, Gandarillas Solinis, Alberto
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/32748
Acceso en línea:https://hdl.handle.net/10902/32748
Access Level:acceso abierto
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spelling DNA damage signalling histone H2AX is required for tumour growthContreras Lara, Lizbeth AraceliGarcía Gaipo, Lorena|||0000-0002-5998-0344Casar Martínez, BertaGandarillas Solinis, AlbertoCancer most frequently develops in self-renewal tissues that are the target of genetic alterations due to mutagens or intrinsic DNA replication errors. Histone γH2AX has a critical role in the cellular DNA repair pathway cascade and contributes to genomic stability. However, the role of γH2AX in the ontology of cancer is unclear. We have investigated this issue in the epidermis, a self-renewal epithelium continuously exposed to genetic hazard and replication stress. Silencing H2AX caused cell cycle hyperactivation, impaired DNA repair and epidermal hyperplasia in the skin. However, mutagen-induced carcinogenesis was strikingly reduced in the absence of H2AX. KO tumours appeared significantly later than controls and were fewer, smaller and more benign. The stem cell marker Δp63 drastically diminished in the KO epidermis. We conclude that H2AX is required for tissue-making during both homoeostasis and tumourigenesis, possibly by contributing to the control and repair of stem cells. Therefore, although H2AX is thought to act as a tumour suppressor and our results show that it contributes to homeostasis, they also indicate that it is required for the development of cancer.ACKNOWLEDGEMENTS: We thank Andre Nussenzweig for kindly giving permission to study the H2AX KO mice and Jaime Font de Mora for sharing them. We thank Alicia Noriega, Lara Grande, Angel Saiz, Iris Aja and Ana Marcos for technical support, Miguel García for assistance in animal care and Victor Campa for kind support in image management. This work was funded by grants from Instituto de Salud Carlos III, ISCIII/FEDER (PI17/01307, PI20/08800, Spain; AG) and from Ministerio de Innovación, Ciencia y Universidades, (MICIU PID2020/112760RB-100; BC). LC was supported by a scholarship from Consejo Nacional de Ciencia y Tecnología (CONACyT; 709426); México).Springer NatureUniversidad de Cantabria20242024-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/32748Cell Death Discovery, 2024, 10, 99reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/327482026-06-02T12:39:31Z
dc.title.none.fl_str_mv DNA damage signalling histone H2AX is required for tumour growth
title DNA damage signalling histone H2AX is required for tumour growth
spellingShingle DNA damage signalling histone H2AX is required for tumour growth
Contreras Lara, Lizbeth Araceli
title_short DNA damage signalling histone H2AX is required for tumour growth
title_full DNA damage signalling histone H2AX is required for tumour growth
title_fullStr DNA damage signalling histone H2AX is required for tumour growth
title_full_unstemmed DNA damage signalling histone H2AX is required for tumour growth
title_sort DNA damage signalling histone H2AX is required for tumour growth
dc.creator.none.fl_str_mv Contreras Lara, Lizbeth Araceli
García Gaipo, Lorena|||0000-0002-5998-0344
Casar Martínez, Berta
Gandarillas Solinis, Alberto
author Contreras Lara, Lizbeth Araceli
author_facet Contreras Lara, Lizbeth Araceli
García Gaipo, Lorena|||0000-0002-5998-0344
Casar Martínez, Berta
Gandarillas Solinis, Alberto
author_role author
author2 García Gaipo, Lorena|||0000-0002-5998-0344
Casar Martínez, Berta
Gandarillas Solinis, Alberto
author2_role author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
description Cancer most frequently develops in self-renewal tissues that are the target of genetic alterations due to mutagens or intrinsic DNA replication errors. Histone γH2AX has a critical role in the cellular DNA repair pathway cascade and contributes to genomic stability. However, the role of γH2AX in the ontology of cancer is unclear. We have investigated this issue in the epidermis, a self-renewal epithelium continuously exposed to genetic hazard and replication stress. Silencing H2AX caused cell cycle hyperactivation, impaired DNA repair and epidermal hyperplasia in the skin. However, mutagen-induced carcinogenesis was strikingly reduced in the absence of H2AX. KO tumours appeared significantly later than controls and were fewer, smaller and more benign. The stem cell marker Δp63 drastically diminished in the KO epidermis. We conclude that H2AX is required for tissue-making during both homoeostasis and tumourigenesis, possibly by contributing to the control and repair of stem cells. Therefore, although H2AX is thought to act as a tumour suppressor and our results show that it contributes to homeostasis, they also indicate that it is required for the development of cancer.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/32748
url https://hdl.handle.net/10902/32748
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://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
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv Cell Death Discovery, 2024, 10, 99
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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