Dicer prevents genome instability in response to replication stress - Institut Gustave Roussy
Article Dans Une Revue Oncotarget Année : 2019

Dicer prevents genome instability in response to replication stress

Résumé

Dicer, an endoribonuclease best-known for its role in microRNA biogenesis and RNA interference pathway, has been shown to play a role in the DNA damage response and repair of double-stranded DNA breaks (DSBs) in mammalian cells. However, it remains unknown whether Dicer is also important to preserve genome integrity upon replication stress. To address this question, we focused our study on common fragile sites (CFSs), which are susceptible to breakage after replication stress. We show that inhibition of the Dicer pathway leads to an increase in CFS expression upon induction of replication stress and to an accumulation of 53BP1 nuclear bodies, indicating transmission of replication-associated damage. We also show that in absence of a functional Dicer or Drosha, the assembly into nuclear foci of the Fanconi anemia (FA) protein FANCD2 and of the replication and checkpoint factor TopBP1 in response to replication stress is impaired, and the activation of the S-phase checkpoint is defective. Based on these results, we propose that Dicer pre-vents genomic instability after replication stress, by allowing the proper recruitment to stalled forks of proteins that are necessary to maintain replication fork stability and activate the S-phase checkpoint, thus limiting cells from proceeding into mitosis with under-replicated DNA.
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Dates et versions

hal-04442048 , version 1 (16-04-2024)

Identifiants

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Michalis Fragkos, Viviana Barra, Tom Egger, Benoit Bordignon, Delphine Lemacon, et al.. Dicer prevents genome instability in response to replication stress. Oncotarget, 2019, 10 (43), pp.4407-4423. ⟨10.18632/oncotarget.27034⟩. ⟨hal-04442048⟩
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