TY - JOUR
T1 - Identification of early replicating fragile sites that contribute to genome instability
AU - Barlow, Jacqueline
AU - Faryabi, Robert B.
AU - Callén, Elsa
AU - Wong, Nancy
AU - Malhowski, Amy
AU - Chen, Hua Tang
AU - Gutierrez-Cruz, Gustavo
AU - Sun, Hong Wei
AU - McKinnon, Peter
AU - Wright, George
AU - Casellas, Rafael
AU - Robbiani, Davide F.
AU - Staudt, Louis
AU - Fernandez-Capetillo, Oscar
AU - Nussenzweig, André
PY - 2013/1/31
Y1 - 2013/1/31
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.01.006
DO - 10.1016/j.cell.2013.01.006
M3 - Article
C2 - 23352430
AN - SCOPUS:84873310832
VL - 152
SP - 620
EP - 632
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -