Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity
Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to level...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2021
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| _version_ | 1797102888242118656 |
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| author | Bader, S Ma, T Simpson, C Liang, J Maezono, SE Olcina, M Buffa, F Hammond, E |
| author_facet | Bader, S Ma, T Simpson, C Liang, J Maezono, SE Olcina, M Buffa, F Hammond, E |
| author_sort | Bader, S |
| collection | OXFORD |
| description | Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B. |
| first_indexed | 2024-03-07T06:12:10Z |
| format | Journal article |
| id | oxford-uuid:efe4f1fd-6372-4ce9-ad88-619f3b72fa0c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:12:10Z |
| publishDate | 2021 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:efe4f1fd-6372-4ce9-ad88-619f3b72fa0c2022-03-27T11:43:42ZReplication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:efe4f1fd-6372-4ce9-ad88-619f3b72fa0cEnglishSymplectic ElementsOxford University Press2021Bader, SMa, TSimpson, CLiang, JMaezono, SEOlcina, MBuffa, FHammond, ETumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B. |
| spellingShingle | Bader, S Ma, T Simpson, C Liang, J Maezono, SE Olcina, M Buffa, F Hammond, E Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity |
| title | Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity |
| title_full | Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity |
| title_fullStr | Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity |
| title_full_unstemmed | Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity |
| title_short | Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity |
| title_sort | replication catastrophe induced by cyclic hypoxia leads to increased apobec3b activity |
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