Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein
Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein
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DOI：
10.1101/gad.279003
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发表时间：
2003-12-15
影响因子：
10.5
通讯作者：
Venkitaraman, AR
中科院分区：
文献类型：
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作者：
Lomonosov, M;Anand, S;Venkitaraman, AR
分裂的哺乳动物细胞如何通过DNA损伤、耗尽的核苷酸库或模板结合蛋白克服DNA复制的障碍尚不清楚。在这里，我们表明，阻断复制的反应需要BRCA2，人类乳腺癌的抑制因子。通过使用二维凝胶电泳，我们证明了在BRCA2缺陷细胞的全基因组复制停滞期间，停滞复制叉处的Y形DNA连接消失，伴随着双链DNA断裂。但是复制检查点激酶Chk2的激活不受影响，这就定义了BRCA2在稳定停滞分叉处的DNA结构方面的意想不到的功能。我们提出，在BRCA2缺陷和相关的染色体不稳定性疾病中，复制叉的破坏，在正常细胞生长期间停止或暂停，触发自发的DNA断裂，导致突变和癌症易感性。
How dividing mammalian cells overcome blocks to DNA replication by DNA damage, depleted nucleotide pools, or template-bound proteins is unclear. Here, we show that the response to blocked replication requires BRCA2, a suppressor of human breast cancer. By using two-dimensional gel electrophoresis, we demonstrate that Y-shaped DNA junctions at stalled replication forks disappear during genome-wide replication arrest in BRCA2-deficient cells, accompanied by double-strand DNA breakage. But activation of the replication checkpoint kinase Chk2 is unaffected, defining an unexpected function for BRCA2 in stabilizing DNA structures at stalled forks. We propose that in BRCA2 deficiency and related chromosomal instability diseases, the breakdown of replication forks, which arrest or pause during normal cell growth, triggers spontaneous DNA breakage, leading to mutability and cancer predisposition.