Identification of early replicating fragile sites that contribute to genome instability.
Identification of early replicating fragile sites that contribute to genome instability.
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DOI：
10.1016/j.cell.2013.01.006
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发表时间：
2013-01-31
期刊：
影响因子：
64.5
通讯作者：
Nussenzweig A
中科院分区：
文献类型：
--
作者：
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
B淋巴细胞DNA双链断裂（DNA double strand breaks，DSB）是在复制过程中随机发生的，也是激活诱导的胞苷脱氨酶（cytidine deaminase，AID）靶向DNA损伤的结果。在这里，我们确定复发，早期复制和AID独立的DNA损伤，称为早期复制脆性位点（ERFS），DNA修复蛋白在B细胞复制应激的全基因组定位。ERFS与高表达的基因簇共定位，并富含重复元件和CpG二核苷酸。尽管与晚期复制常见脆性位点（CFS）不同，但ERFS和CFS的稳定性同样依赖于复制应激反应激酶ATR。ERFS在复制过程中自发断裂，但它们的脆性会因羟基脲、ATR抑制或c-Myc表达失调而增加。此外，在人弥漫性大B细胞淋巴瘤中超过50%的复发性扩增/缺失映射到ERFS。总之，我们已经确定了一个自发DNA损伤的来源，驱动不稳定的首选基因组位点。
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 (ERFS), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFS 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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