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 language | English (US) |
|---|---|
| Pages (from-to) | 620-632 |
| Number of pages | 13 |
| Journal | Cell |
| Volume | 152 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 31 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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 journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=84873310832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873310832&partnerID=8YFLogxK
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 -