EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2.
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Date
2019-08-08ICR Author
Author
Nieminuszczy, J
Broderick, R
Bellani, MA
Smethurst, E
Schwab, RA
Cherdyntseva, V
Evmorfopoulou, T
Lin, Y-L
Minczuk, M
Pasero, P
Gagos, S
Seidman, MM
Niedzwiedz, W
Type
Journal Article
Metadata
Show full item recordAbstract
Accurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including cancer. Key to this process is the cells' ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this process. EXD2 recruitment to stressed forks suppresses their degradation by restraining excessive fork regression. Accordingly, EXD2 deficiency leads to fork collapse, hypersensitivity to replication inhibitors, and genomic instability. Impeding fork regression by inactivation of SMARCAL1 or removal of RECQ1's inhibition in EXD2-/- cells restores efficient fork restart and genome stability. Moreover, purified EXD2 efficiently processes substrates mimicking regressed forks. Thus, this work identifies a mechanism underpinned by EXD2's nuclease activity, by which cells balance fork regression with fork restoration to maintain genome stability. Interestingly, from a clinical perspective, we discover that EXD2's depletion is synthetic lethal with mutations in BRCA1/2, implying a non-redundant role in replication fork protection.
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Subject
Hela Cells
Humans
Neoplasms
Genomic Instability
Exodeoxyribonucleases
DNA Helicases
BRCA1 Protein
BRCA2 Protein
DNA Replication
RecQ Helicases
Synthetic Lethal Mutations
Research team
Cancer and Genome Instability
Language
eng
Date accepted
2019-05-17
License start date
2019-08
Citation
Molecular cell, 2019, 75 (3), pp. 605 - 619.e6
Publisher
CELL PRESS