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Cell. 2013 Jan 31;152(3):620-32. doi: 10.1016/j.cell.2013.01.006. Epub 2013 Jan 24.

Identification of early replicating fragile sites that contribute to genome instability.

Author information

1
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.

Abstract

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 (ERFSs), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFSs 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.

PMID:
23352430
PMCID:
PMC3629730
DOI:
10.1016/j.cell.2013.01.006
[Indexed for MEDLINE]
Free PMC Article

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