Identification of early replicating fragile sites that contribute to genome instability.

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.

journal_name

Cell

journal_title

Cell

authors

Barlow JH,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

doi

10.1016/j.cell.2013.01.006

subject

Has Abstract

pub_date

2013-01-31 00:00:00

pages

620-32

issue

3

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(13)00008-1

journal_volume

152

pub_type

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