p53 coordinates base excision repair to prevent genomic instability
DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these proc...
| Main Authors: | , , , |
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| Format: | Journal article |
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Oxford University Press
2016
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| _version_ | 1797106265490456576 |
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| author | Poletto, M Legrand, A Fletcher, S Dianov, G |
| author_facet | Poletto, M Legrand, A Fletcher, S Dianov, G |
| author_sort | Poletto, M |
| collection | OXFORD |
| description | DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells. |
| first_indexed | 2024-03-07T06:59:16Z |
| format | Journal article |
| id | oxford-uuid:ff2e8750-8e61-4725-a040-c2625b13f7ba |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:59:16Z |
| publishDate | 2016 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:ff2e8750-8e61-4725-a040-c2625b13f7ba2022-03-27T13:42:44Zp53 coordinates base excision repair to prevent genomic instabilityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ff2e8750-8e61-4725-a040-c2625b13f7baSymplectic Elements at OxfordOxford University Press2016Poletto, MLegrand, AFletcher, SDianov, GDNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells. |
| spellingShingle | Poletto, M Legrand, A Fletcher, S Dianov, G p53 coordinates base excision repair to prevent genomic instability |
| title | p53 coordinates base excision repair to prevent genomic instability |
| title_full | p53 coordinates base excision repair to prevent genomic instability |
| title_fullStr | p53 coordinates base excision repair to prevent genomic instability |
| title_full_unstemmed | p53 coordinates base excision repair to prevent genomic instability |
| title_short | p53 coordinates base excision repair to prevent genomic instability |
| title_sort | p53 coordinates base excision repair to prevent genomic instability |
| work_keys_str_mv | AT polettom p53coordinatesbaseexcisionrepairtopreventgenomicinstability AT legranda p53coordinatesbaseexcisionrepairtopreventgenomicinstability AT fletchers p53coordinatesbaseexcisionrepairtopreventgenomicinstability AT dianovg p53coordinatesbaseexcisionrepairtopreventgenomicinstability |