SMARCAD1-mediated active replication fork stability maintains genome integrity

Calvin Shun Yu Lo, Marvin van Toorn, Vincent Gaggioli, Mariana Paes Dias, Yifan Zhu, Eleni Maria Manolika, Wei Zhao, Marit van der Does, Chirantani Mukherjee, João G.S.C. Souto Gonçalves, Martin E. van Royen, Pim J. French, Jeroen Demmers, Ihor Smal, Hannes Lans, David Wheeler, Jos Jonkers, Arnab Ray Chaudhuri, Jurgen A. Marteijn, Nitika Taneja*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
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Abstract

The stalled fork protection pathway mediated by breast cancer 1/2 (BRCA1/2) proteins is critical for replication fork stability. However, it is unclear whether additional mechanisms are required to maintain replication fork stability. We describe a hitherto unknown mechanism, by which the SWI/SNF-related matrix-associated actindependent regulator of chromatin subfamily-A containing DEAD/H box-1 (SMARCAD1) stabilizes active replication forks, that is essential to maintaining resistance towards replication poisons. We find that SMARCAD1 prevents accumulation of 53BP1-associated nucleosomes to preclude toxic enrichment of 53BP1 at the forks. In the absence of SMARCAD1, 53BP1 mediates untimely dissociation of PCNA via the PCNA-unloader ATAD5, causing frequent fork stalling, inefficient fork restart, and accumulation of single-stranded DNA. Although loss of 53BP1 in SMARCAD1 mutants rescues these defects and restores genome stability, this rescued stabilization also requires BRCA1-mediated fork protection. Notably, fork protection-challenged BRCA1-deficient naïve- or chemoresistant tumors require SMARCAD1-mediated active fork stabilization to maintain unperturbed fork progression and cellular proliferation.

Original languageEnglish
Article numbereabe7804
JournalScience advances
Volume7
Issue number19
DOIs
Publication statusPublished - 5 May 2021

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