DOI: 10.1101/gad.279003. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein

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

10.1101/gad.279003

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

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.

Bibliography

Lomonosov, M., Anand, S., Sangrithi, M., Davies, R., & Venkitaraman, A. R. (2003). Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes & Development, 17(24), 3017â3022.

Authors 5

Mikhail Lomonosov (first)
Shubha Anand (additional)
Mahesh Sangrithi (additional)
Rachel Davies (additional)
Ashok R. Venkitaraman (additional)

References 36 Referenced 199

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Dates

Type	When
Created	21 years, 8 months ago (Dec. 22, 2003, 8:13 p.m.)
Deposited	3 years, 9 months ago (Nov. 15, 2021, 10:36 p.m.)
Indexed	14 hours, 19 minutes ago (Sept. 6, 2025, 4:10 p.m.)
Issued	22 years, 8 months ago (Jan. 1, 2003)
Published	22 years, 8 months ago (Jan. 1, 2003)
Published Online	22 years, 8 months ago (Jan. 1, 2003)
Published Print	21 years, 8 months ago (Dec. 15, 2003)

Funders 0

None

BibTeX

@article{Lomonosov_2003, title={Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein}, volume={17}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.279003}, DOI={10.1101/gad.279003}, number={24}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Lomonosov, Mikhail and Anand, Shubha and Sangrithi, Mahesh and Davies, Rachel and Venkitaraman, Ashok R.}, year={2003}, month=jan, pages={3017–3022} }

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