Identification of early replicating fragile sites that contribute to genome instability

Jacqueline Barlow, Robert B. Faryabi, Elsa Callén, Nancy Wong, Amy Malhowski, Hua Tang Chen, Gustavo Gutierrez-Cruz, Hong Wei Sun, Peter McKinnon, George Wright, Rafael Casellas, Davide F. Robbiani, Louis Staudt, Oscar Fernandez-Capetillo, André Nussenzweig

Research output: Contribution to journalArticle

221 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)620-632
Number of pages13
JournalCell
Volume152
Issue number3
DOIs
StatePublished - Jan 31 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Barlow, J., Faryabi, R. B., Callén, E., Wong, N., Malhowski, A., Chen, H. T., Gutierrez-Cruz, G., Sun, H. W., McKinnon, P., Wright, G., Casellas, R., Robbiani, D. F., Staudt, L., Fernandez-Capetillo, O., & Nussenzweig, A. (2013). Identification of early replicating fragile sites that contribute to genome instability. Cell, 152(3), 620-632. https://doi.org/10.1016/j.cell.2013.01.006