期刊
GENES & DEVELOPMENT
卷 17, 期 24, 页码 3017-3022出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.279003
关键词
cancer susceptibility; cell cycle checkpoints; chromosome structure; DNA replication; genetic instability
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.
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