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 naïve-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.
Lo, Calvin Shun Yu and van Toorn, Marvin and Gaggioli, Vincent and Dias, Mariana Paes and Zhu, Yifan and Manolika, Eleni Maria and Zhao, Wei and van der Does, Marit and Mukherjee, Chirantani and Souto Gonçalves, João G. S. C. and van Royen, Martin E. and French, Pim J. and Demmers, Jeroen A.A. and Smal, Ihor and Lans, Hannes and Wheeler, David and Jonkers, Jos and Ray Chaudhuri, Arnab and Marteijn, Jurgen A. and Taneja, Nitika, Interplay of SMARCAD1 and BRCA1 at Replication Forks to Maintain Genome Integrity. Available at SSRN: https://ssrn.com/abstract=3581365 or http://dx.doi.org/10.2139/ssrn.3581365
This version of the paper has not been formally peer reviewed.
Download This Paper