| Autor: |
Hannes Lans, Nitika Taneja, Yifan Zhu, Arnab Ray Chaudhuri, Martin E. van Royen, Calvin Shun Yu Lo, Eleni Maria Manolika, Jos Jonkers, Chirantani Mukherjee, Marvin van Toorn, Vincent Gaggioli, David C. Wheeler, Wei Zhao, Ihor Smal, João G. S. C. Souto Gonçalves, Jurgen A. Marteijn, Jeroen Demmers, Mariana Paes Dias, Marit van der Does, Pim J. French |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| Popis: |
Chemotherapeutic regimens that poison DNA replication are used for the treatment of homologous recombination (HR)-deficient cancers. We have discovered a novel mechanism by which the SWI/SNF chromatin remodeler SMARCAD1 stabilizes replication forks that is essential for resistance towards replication poisons. We find that loss of SMARCAD1 results in toxic enrichment of 53BP1 at replication forks which mediates untimely dissociation of PCNA via the PCNA-unloader, ATAD5. Faster dissociation of PCNA causes frequent fork stalling, inefficient fork restart and accumulation of single-stranded DNA resulting in genome instability. Although, loss of 53BP1 in SMARCAD1 mutants restore PCNA levels, fork restart efficiency, genome stability and resistance to replication poisons, this requires BRCA1 mediated fork protection. Interestingly, fork protection challenged BRCA1-deficient naive-or PARPi-resistant tumors require SMARCAD1 mediated fork stabilization to maintain cellular proliferation. Our data reveal a critical interplay between SMARCAD1 mediated fork stabilization and BRCA1 mediated fork protection in maintenance of genome stability. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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