Oncotarget

Research Papers:

Dicer prevents genome instability in response to replication stress

Michalis Fragkos _, Viviana Barra, Tom Egger, Benoit Bordignon, Delphine Lemacon, Valeria Naim _ and Arnaud Coquelle _

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Oncotarget. 2019; 10:4407-4423. https://doi.org/10.18632/oncotarget.27034

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Abstract

Michalis Fragkos1,2,*, Viviana Barra2,*, Tom Egger1, Benoit Bordignon1, Delphine Lemacon1,3, Valeria Naim2,# and Arnaud Coquelle1

1 IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France

2 Laboratory of Genetic Instability and Oncogenesis, UMR 8200 CNRS, University Paris-Sud, Gustave Roussy, Villejuif, France

3 Present address: Department of Biochemistry and Molecular Biology, Doisy Research Center, St. Louis, MO, USA

* These authors contributed equally to this work

# Lead contact

Correspondence to:

Valeria Naim,email: valeria.naim@gustaveroussy.fr
Arnaud Coquelle,email: arnaud.coquelle@inserm.fr
Michalis Fragkos,email: michail.fragkos@gmail.com

Keywords: replication stress; common fragile sites; Dicer; genomic instability

Received: November 22, 2018     Accepted: June 05, 2019     Published: July 09, 2019

ABSTRACT

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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