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SMARCAD1-mediated active replication fork stability maintains genome integrity
- Source :
- Science advances, 7(19):eabe7804. American Association for the Advancement of Science
- Publication Year :
- 2021
-
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.
- Subjects :
- Genome instability
Genome integrity
Mutant
Regulator
Biology
medicine.disease_cause
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
SDG 3 - Good Health and Well-being
medicine
Nucleosome
Genome stability
030304 developmental biology
0303 health sciences
Multidisciplinary
Replication (computing)
Proliferating cell nuclear antigen
Chromatin
Cell biology
chemistry
030220 oncology & carcinogenesis
Fork (system call)
biology.protein
Carcinogenesis
DNA
Subjects
Details
- Language :
- English
- ISSN :
- 23752548
- Volume :
- 7
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Science advances
- Accession number :
- edsair.doi.dedup.....d1caca7d1a9acf15b182b293d6934596