Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load
Ultraviolet radiation‐induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV‐induced lesions, that is, the nucleotide excision r...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-01-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12601 |
| _version_ | 1819225157393186816 |
|---|---|
| author | Sandra Pavey Alex Pinder Winnie Fernando Nicholas D’Arcy Nicholas Matigian Dubravka Skalamera Kim‐Anh Lê Cao Dorothy Loo‐Oey Michelle M. Hill Mitchell Stark Michael Kimlin Andrew Burgess Nicole Cloonan Richard A. Sturm Brian Gabrielli |
| author_facet | Sandra Pavey Alex Pinder Winnie Fernando Nicholas D’Arcy Nicholas Matigian Dubravka Skalamera Kim‐Anh Lê Cao Dorothy Loo‐Oey Michelle M. Hill Mitchell Stark Michael Kimlin Andrew Burgess Nicole Cloonan Richard A. Sturm Brian Gabrielli |
| author_sort | Sandra Pavey |
| collection | DOAJ |
| description | Ultraviolet radiation‐induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV‐induced lesions, that is, the nucleotide excision repair pathway, appears intact in most melanomas. We have previously reported a postreplication repair mechanism that is commonly defective in melanoma cell lines. Here we have used a genome‐wide approach to identify the components of this postreplication repair mechanism. We have used differential transcript polysome loading to identify transcripts that are associated with UV response, and then functionally assessed these to identify novel components of this repair and cell cycle checkpoint network. We have identified multiple interaction nodes, including global genomic nucleotide excision repair and homologous recombination repair, and previously unexpected MASTL pathway, as components of the response. Finally, we have used bioinformatics to assess the contribution of dysregulated expression of these pathways to the UV signature mutation load of a large melanoma cohort. We show that dysregulation of the pathway, especially the DNA damage repair components, are significant contributors to UV mutation load, and that dysregulation of the MASTL pathway appears to be a significant contributor to high UV signature mutation load. |
| first_indexed | 2024-12-23T10:05:08Z |
| format | Article |
| id | doaj.art-8d2a9fd8b0b2495fa4df352e0cc21d2c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-23T10:05:08Z |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-8d2a9fd8b0b2495fa4df352e0cc21d2c2022-12-21T17:51:06ZengWileyMolecular Oncology1574-78911878-02612020-01-01141224110.1002/1878-0261.12601Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation loadSandra Pavey0Alex Pinder1Winnie Fernando2Nicholas D’Arcy3Nicholas Matigian4Dubravka Skalamera5Kim‐Anh Lê Cao6Dorothy Loo‐Oey7Michelle M. Hill8Mitchell Stark9Michael Kimlin10Andrew Burgess11Nicole Cloonan12Richard A. Sturm13Brian Gabrielli14Diamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaMater Research TRI The University of Queensland Woolloongabba QLD AustraliaMater Research TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaUniversity of the Sunshine Coast Sippy Downs QLD AustraliaANZAC Research Institute Concord NSW AustraliaQIMR Berghofer Medical Research Institute Herston QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaDiamantina Institute TRI The University of Queensland Woolloongabba QLD AustraliaUltraviolet radiation‐induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV‐induced lesions, that is, the nucleotide excision repair pathway, appears intact in most melanomas. We have previously reported a postreplication repair mechanism that is commonly defective in melanoma cell lines. Here we have used a genome‐wide approach to identify the components of this postreplication repair mechanism. We have used differential transcript polysome loading to identify transcripts that are associated with UV response, and then functionally assessed these to identify novel components of this repair and cell cycle checkpoint network. We have identified multiple interaction nodes, including global genomic nucleotide excision repair and homologous recombination repair, and previously unexpected MASTL pathway, as components of the response. Finally, we have used bioinformatics to assess the contribution of dysregulated expression of these pathways to the UV signature mutation load of a large melanoma cohort. We show that dysregulation of the pathway, especially the DNA damage repair components, are significant contributors to UV mutation load, and that dysregulation of the MASTL pathway appears to be a significant contributor to high UV signature mutation load.https://doi.org/10.1002/1878-0261.12601DNA repairG2 phase checkpointMASTLpostreplication repairultraviolet radiation |
| spellingShingle | Sandra Pavey Alex Pinder Winnie Fernando Nicholas D’Arcy Nicholas Matigian Dubravka Skalamera Kim‐Anh Lê Cao Dorothy Loo‐Oey Michelle M. Hill Mitchell Stark Michael Kimlin Andrew Burgess Nicole Cloonan Richard A. Sturm Brian Gabrielli Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load Molecular Oncology DNA repair G2 phase checkpoint MASTL postreplication repair ultraviolet radiation |
| title | Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load |
| title_full | Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load |
| title_fullStr | Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load |
| title_full_unstemmed | Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load |
| title_short | Multiple interaction nodes define the postreplication repair response to UV‐induced DNA damage that is defective in melanomas and correlated with UV signature mutation load |
| title_sort | multiple interaction nodes define the postreplication repair response to uv induced dna damage that is defective in melanomas and correlated with uv signature mutation load |
| topic | DNA repair G2 phase checkpoint MASTL postreplication repair ultraviolet radiation |
| url | https://doi.org/10.1002/1878-0261.12601 |
| work_keys_str_mv | AT sandrapavey multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT alexpinder multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT winniefernando multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT nicholasdarcy multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT nicholasmatigian multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT dubravkaskalamera multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT kimanhlecao multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT dorothyloooey multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT michellemhill multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT mitchellstark multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT michaelkimlin multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT andrewburgess multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT nicolecloonan multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT richardasturm multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload AT briangabrielli multipleinteractionnodesdefinethepostreplicationrepairresponsetouvinduceddnadamagethatisdefectiveinmelanomasandcorrelatedwithuvsignaturemutationload |