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Identification of early replicating fragile sites that contribute to genome instability

Friday, November 08, 2013 — Poster Session IV

2:00 p.m. – 4:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • R.B. Faryabi
  • J.H. Barlow
  • E. Callen
  • R. Casellas
  • L. Staudt
  • O. Fernandez-Capetillo
  • A. Nussenzweig


DNA double strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation induced cytidine deaminase (AID). Here we identify recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFS colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG dinucleotides. Although distinct from late-replicating common fragile sites (CFS), the stability of ERFSs and CFSs is similarly dependent on the replication-stress response kinase ATR. ERFSs break spontaneously during replication, but their fragility is increased by hydroxyurea, ATR inhibition or deregulated c-Myc expression. Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites.

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