p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways
Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/31723 |
| _version_ | 1811236988714483712 |
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| author | Sunetra Roy Karl-Heinz Tomaszowski Jessica W Luzwick Soyoung Park Jun Li Maureen Murphy Katharina Schlacher |
| author_facet | Sunetra Roy Karl-Heinz Tomaszowski Jessica W Luzwick Soyoung Park Jun Li Maureen Murphy Katharina Schlacher |
| author_sort | Sunetra Roy |
| collection | DOAJ |
| description | Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability. |
| first_indexed | 2024-04-12T12:18:13Z |
| format | Article |
| id | doaj.art-d59ddfa5c38f4f2cae38704cb46a36dd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:18:13Z |
| publishDate | 2018-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d59ddfa5c38f4f2cae38704cb46a36dd2022-12-22T03:33:22ZengeLife Sciences Publications LtdeLife2050-084X2018-01-01710.7554/eLife.31723p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathwaysSunetra Roy0Karl-Heinz Tomaszowski1Jessica W Luzwick2Soyoung Park3Jun Li4Maureen Murphy5https://orcid.org/0000-0001-7644-7296Katharina Schlacher6https://orcid.org/0000-0001-7226-6391Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, United StatesDepartment of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, United StatesDepartment of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, United StatesDepartment of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, United StatesDepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, United StatesMolecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, United StatesDepartment of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, United StatesClassically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.https://elifesciences.org/articles/31723p53genome instabilityreplication fork restartMRE11BRCA2replication protection |
| spellingShingle | Sunetra Roy Karl-Heinz Tomaszowski Jessica W Luzwick Soyoung Park Jun Li Maureen Murphy Katharina Schlacher p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways eLife p53 genome instability replication fork restart MRE11 BRCA2 replication protection |
| title | p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways |
| title_full | p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways |
| title_fullStr | p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways |
| title_full_unstemmed | p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways |
| title_short | p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways |
| title_sort | p53 orchestrates dna replication restart homeostasis by suppressing mutagenic rad52 and polθ pathways |
| topic | p53 genome instability replication fork restart MRE11 BRCA2 replication protection |
| url | https://elifesciences.org/articles/31723 |
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