Olivier Brison

ATR and TopBP1 oppose to control dormant origin activity and global replication dynamics, providing a first defense against replication stress

Stéphane Koundrioukoff, Nathan Alary, Su-Jung Kim, Thibault Collin et autres

Replication stress and resulting genome instability, a major driver of cancer progression, stem from perturbations of replication fork progression. The first defense against this stress is activation of "dormant" replication origins, which supports replication completion. To determine whether ATR, in itself, contributes …

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ATR and TopBP1 oppose to control dormant origin building, providing a first defence against replication stress

Michelle Debatisse, Stéphane Koundrioukoff, Su‐Jung Kim, Nathan Alary et autres

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The balance between ATR and DDK activities controls TopBP1-mediated locking of dormant origins at the pre-IC stage

Stéphane Koundrioukoff, Su-Jung Kim, Nathan Alary, Antoine Toffano et autres

Summary Replication stress, a major hallmark of cancers, and ensuing genome instability source from impaired progression of replication forks. The first line of defense against fork slowing is compensation, a long-described process that elicits firing of otherwise dormant origins. It remains unclear …

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Mistimed origin licensing and activation stabilize common fragile sites under tight DNA-replication checkpoint activation

Olivier Brison, Stefano Gnan, Dana Azar, Stéphane Koundrioukoff et autres

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Unscheduled origin building in S-phase upon tight CDK1 inhibition suppresses CFS instability

Olivier Brison, Stefano Gnan, Dana Azar, Mélanie Schmidt et autres

Summary Genome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs) however escapes surveillance, which triggers chromosome breakage. Using …

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Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide

Olivier Brison, Sami El Hilali, Dana Azar, Stéphane Koundrioukoff et autres

Common fragile sites (CFSs) are chromosome regions prone to breakage upon replication stress known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription could elicit their instability; however, the underlying mechanisms remain elusive. Genome-wide replication …

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Transcription-mediated organization of the replication initiation program across large genes sets up common fragile sites genome-wide

Olivier Brison, Sami El Hilali, Dana Azar, Stéphane Koundrioukoff et autres

ABSTRACT Common Fragile Sites (CFSs) are chromosome regions prone to breakage under replication stress, known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription elicits their instability but the underlying mechanisms remained elusive. Analyses of …

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Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage

Hervé Técher, Stéphane Koundrioukoff, Sandra Carignon, Therese Wilhelm et autres

Mammalian cells deficient in ATR or Chk1 display moderate replication fork slowing and increased initiation density, but the underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both replication phenotypes in Chk1-deficient, but not ATR-deficient, cells. Thus, in the absence …

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Updating the mechanisms of common fragile site instability: how to reconcile the different views?

Benoît Le Tallec, Stéphane Koundrioukoff, Therese Wilhelm, A Letessier et autres

Common fragile sites (CFSs) are large chromosomal regions long identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs came from their key role in the formation of DNA damage, resulting in chromosomal …

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Common Fragile Site Profiling in Epithelial and Erythroid Cells Reveals that Most Recurrent Cancer Deletions Lie in Fragile Sites Hosting Large Genes

Benoît Le Tallec, Gaël A. Millot, Marion Blin, Olivier Brison et autres

Cancer genomes exhibit numerous deletions, some of which inactivate tumor suppressor genes and/or correspond to unstable genomic regions, notably common fragile sites (CFSs). However, 70%-80% of recurrent deletions cataloged in tumors remain unexplained. Recent findings that CFS setting is cell-type dependent prompted …

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Stepwise Activation of the ATR Signaling Pathway upon Increasing Replication Stress Impacts Fragile Site Integrity

Stéphane Koundrioukoff, Sandra Carignon, Hervé Técher, A Letessier et autres

Breaks at common fragile sites (CFS) are a recognized source of genome instability in pre-neoplastic lesions, but how such checkpoint-proficient cells escape surveillance and continue cycling is unknown. Here we show, in lymphocytes and fibroblasts, that moderate replication stresses like those inducing …

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Characterization at nucleotide resolution of the homogeneously staining region sites of insertion in two cancer cell lines

Anne Gibaud, Nicolas Vogt, Olivier Brison, Michelle Debatisse et autres

The mechanisms of formation of intrachromosomal amplifications in tumours are still poorly understood. By using quantitative polymerase chain reaction, DNA sequencing, chromosome walking, in situ hybridization on metaphase chromosomes and whole-genome analysis, we studied two cancer cell lines containing an MYC oncogene …

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