Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein.

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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Lomonosov M,Anand S,Sangrithi M,Davies R,Venkitaraman AR

doi

10.1101/gad.279003

subject

Has Abstract

pub_date

2003-12-15 00:00:00

pages

3017-22

issue

24

eissn

0890-9369

issn

1549-5477

pii

279003

journal_volume

17

pub_type

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