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

209 Citations (Scopus)

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

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Genomic Instability
B-Lymphocytes
Genes
Hydroxyurea
Double-Stranded DNA Breaks
Lymphoma, Large B-Cell, Diffuse
DNA
Multigene Family
DNA Repair
DNA Damage
Phosphotransferases
Genome
Cells
Lymphocytes
Amplification
Repair
AICDA (activation-induced cytidine deaminase)
Proteins
IgA receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Barlow, J., Faryabi, R. B., Callén, E., Wong, N., Malhowski, A., Chen, H. T., ... 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

Identification of early replicating fragile sites that contribute to genome instability. / Barlow, Jacqueline; Faryabi, Robert B.; Callén, Elsa; Wong, Nancy; Malhowski, Amy; Chen, Hua Tang; Gutierrez-Cruz, Gustavo; Sun, Hong Wei; McKinnon, Peter; Wright, George; Casellas, Rafael; Robbiani, Davide F.; Staudt, Louis; Fernandez-Capetillo, Oscar; Nussenzweig, André.

In: Cell, Vol. 152, No. 3, 31.01.2013, p. 620-632.

Research output: Contribution to journalArticle

Barlow, J, Faryabi, RB, Callén, E, Wong, N, Malhowski, A, Chen, HT, Gutierrez-Cruz, G, Sun, HW, McKinnon, P, Wright, G, Casellas, R, Robbiani, DF, Staudt, L, Fernandez-Capetillo, O & Nussenzweig, A 2013, 'Identification of early replicating fragile sites that contribute to genome instability', Cell, vol. 152, no. 3, pp. 620-632. https://doi.org/10.1016/j.cell.2013.01.006
Barlow, Jacqueline ; Faryabi, Robert B. ; Callén, Elsa ; Wong, Nancy ; Malhowski, Amy ; Chen, Hua Tang ; Gutierrez-Cruz, Gustavo ; Sun, Hong Wei ; McKinnon, Peter ; Wright, George ; Casellas, Rafael ; Robbiani, Davide F. ; Staudt, Louis ; Fernandez-Capetillo, Oscar ; Nussenzweig, André. / Identification of early replicating fragile sites that contribute to genome instability. In: Cell. 2013 ; Vol. 152, No. 3. pp. 620-632.
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