Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein
AUTOR(ES)
Lomonosov, Mikhail
FONTE
Cold Spring Harbor Laboratory Press
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=305253Documentos Relacionados
- BRCA2 mutation carriers, reproductive factors and breast cancer risk
- Interaction between the Product of the Breast Cancer Susceptibility Gene BRCA2 and DSS1, a Protein Functionally Conserved from Yeast to Mammals
- DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1
- Contribution of BRCA1 and BRCA2 Mutations to Breast and Ovarian Cancer in Pakistan
- BRCA1 and BRCA2 mutations in a population-based study of male breast cancer