Identification of early replicating fragile sites that contribute to genome instability.
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.
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Jacqueline H
JH
Barlow
Robert B
RB
Faryabi
Elsa
E
Callén
Nancy
N
Wong
Amy
A
Malhowski
Hua Tang
HT
Chen
Gustavo
G
Gutierrez-Cruz
Hong-Wei
HW
Sun
Peter
P
McKinnon
George
G
Wright
Rafael
R
Casellas
Davide F
DF
Robbiani
Louis
L
Staudt
Oscar
O
Fernandez-Capetillo
André
A
Nussenzweig
D000818:Animals; D001696:Biomechanical Phenomena; D043283:Chromosome Fragile Sites; D004260:DNA Repair; D004261:DNA Replication; D056890:Eukaryota / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D011387:Prokaryotic Cells / Q000502:physiology*