Abstract

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.

Keywords

BiologyDNA replicationControl of chromosome duplicationPre-replication complexDNA re-replicationEukaryotic DNA replicationCell biologyOrigin recognition complexDNA damageGenome instabilityGeneticsDNADNA replication factor CDT1Molecular biology

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Publication Info

Year
2003
Type
article
Volume
17
Issue
24
Pages
3017-3022
Citations
242
Access
Closed

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Mikhail Lomonosov, Shubha Anand, Mahesh Sangrithi et al. (2003). Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes & Development , 17 (24) , 3017-3022. https://doi.org/10.1101/gad.279003

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DOI
10.1101/gad.279003