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PMID: 14681210 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Genes & development ·Vol. 17 ·No. 24 ·2003-12-15 ·Pages 3017-22

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

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.

MeSH Terms
Animals BRCA2 Protein/physiology Breast Neoplasms/genetics,metabolism Cell Cycle/physiology Cells, Cultured Checkpoint Kinase 2 DNA/chemistry,drug effects,metabolism DNA Damage DNA Repair/genetics,physiology DNA Replication Disease Susceptibility Electrophoresis, Gel, Two-Dimensional Enzyme Inhibitors/pharmacology Female Fibroblasts/metabolism Hydroxyurea/pharmacology Mice Mice, Knockout Phosphorylation Protein Serine-Threonine Kinases/metabolism Replication Origin
Chemicals
BRCA2 Protein Enzyme Inhibitors DNA Checkpoint Kinase 2 CHEK2 protein, human Chek2 protein, mouse Protein Serine-Threonine Kinases Hydroxyurea
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lomonosov Mikhail
University of Cambridge, CR UK Department of Oncology, Hutchison/MRC Research Centre, Cambridge CB2 2XZ, UK.
Anand Shubha
Sangrithi Mahesh
Davies Rachel
Venkitaraman Ashok R
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.279003
Published
2003-12-15
Epub
2003-00-17
Pages
3017-22
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC305253
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.279003 PMC Full Text View journal details
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