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...
| Authors: | ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2024 |
| Country: | España |
| Institution: | Universidad de Cantabria (UC) |
| Repository: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Language: | English |
| OAI Identifier: | oai:repositorio.unican.es:10902/32748 |
| Online Access: | https://hdl.handle.net/10902/32748 |
| Access Level: | Open access |
| _version_ | 1878742890518151168 |
|---|---|
| author | Contreras Lara, Lizbeth Araceli |
| author2 | García Gaipo, Lorena|||0000-0002-5998-0344 Casar Martínez, Berta Gandarillas Solinis, Alberto |
| author2_role | author author author |
| author_browse | Casar Martínez, Berta Contreras Lara, Lizbeth Araceli Gandarillas Solinis, Alberto García Gaipo, Lorena|||0000-0002-5998-0344 |
| author_facet | Contreras Lara, Lizbeth Araceli García Gaipo, Lorena|||0000-0002-5998-0344 Casar Martínez, Berta Gandarillas Solinis, Alberto |
| author_role | author |
| collection | UCrea Repositorio Abierto de la 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_fe1bb48306f7bc9a37dec7feddcf9dbd |
| institution | Universidad de Cantabria (UC) |
| instname_str | Universidad de Cantabria (UC) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repositorio.unican.es:10902/32748 |
| publishDate | 2024 |
| publishDateSort | 2024 |
| publisher | Springer Nature |
| publisherStr | Springer Nature |
| reponame_str | UCrea Repositorio Abierto de la Universidad de Cantabria |
| spelling | DNA damage signalling histone H2AX is required for tumour growth Contreras Lara, Lizbeth Araceli García Gaipo, Lorena|||0000-0002-5998-0344 Casar Martínez, Berta Gandarillas Solinis, Alberto 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. 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 Nature https://hdl.handle.net/10902/32748 |
| spellingShingle | DNA damage signalling histone H2AX is required for tumour growth Contreras Lara, Lizbeth Araceli |
| title | 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_short | DNA damage signalling histone H2AX is required for tumour growth |
| title_sort | DNA damage signalling histone H2AX is required for tumour growth |
| url | https://hdl.handle.net/10902/32748 |