TY - JOUR
T1 - SMARCAD1-mediated active replication fork stability maintains genome integrity
AU - Lo, Calvin Shun Yu
AU - van Toorn, Marvin
AU - Gaggioli, Vincent
AU - Dias, Mariana Paes
AU - Zhu, Yifan
AU - Manolika, Eleni Maria
AU - Zhao, Wei
AU - van der Does, Marit
AU - Mukherjee, Chirantani
AU - Souto Gonçalves, João G.S.C.
AU - van Royen, Martin E.
AU - French, Pim J.
AU - Demmers, Jeroen
AU - Smal, Ihor
AU - Lans, Hannes
AU - Wheeler, David
AU - Jonkers, Jos
AU - Chaudhuri, Arnab Ray
AU - Marteijn, Jurgen A.
AU - Taneja, Nitika
N1 - Publisher Copyright:
© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2021/5/5
Y1 - 2021/5/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105516477&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abe7804
DO - 10.1126/sciadv.abe7804
M3 - Article
C2 - 33952518
AN - SCOPUS:85105516477
SN - 2375-2548
VL - 7
JO - Science advances
JF - Science advances
IS - 19
M1 - eabe7804
ER -
