The Oncologist, Vol. 10, No. 7, 555-556, August 2005; doi:10.1634/theoncologist.10-7-555
© 2005 AlphaMed Press
Fundamentals of Cancer Medicine |
The Molecular Perspective: RAD51 and BRCA2
David S. Goodsell
Correspondence:
David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu; Web site: http://www.scripps.edu/pub/goodsell
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Discuss homologous recombination and its role in cancer.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Redundancy is a powerful method to control errors, and living cells take full advantage of redundancy to protect and repair their genomes. DNA strands are delicate, and they face many challenges. Environmental dangers, such as ionizing radiation, can break DNA strands. DNA polymerase occasionally stalls during replication, for instance at palindromic sequences that form hairpins, leaving the separated DNA strands unprotected and prone to damage. Our cells also break their DNA on purpose to perform rearrangements during meiosis or as they build new antibody genes.
Our cells have two methods to patch broken DNA strands back together. As described in the last Molecular Perspective, the process of nonhomologous end joining may be used to reconnect the strands, but at the cost of introducing some errors. The second method, homologous recombination, takes advantage of the diploid genome to repair broken DNA, using the (approximately) duplicate copy of each chromosome as a backup. Because a duplicate copy is used, homologous recombination is far more accurate in its repairs.
The central step of homologous recombination is synapsis, the process of bringing together the two homologous DNA strands. In synapsis, the intact copy of the DNA is unwound, and the damaged strand is paired with it. Then, the intact strand is used as a template to repair the damaged strand, rebuilding any portions that are missing.
The process of synapsis still holds deep mysteries. Somehow, on a practical time scale, the two homologous regions must find each other from among the billions of competing DNA sequences in the genome. Then, once the homologous sequences are found, the tricky exchange of strands must be performed. The RAD51 protein (Fig. 1
) mediates this daunting task. RAD51, like the related bacterial protein RecA, forms long helical filaments surrounding the DNA. The filament is sufficiently large to hold three DNA strands: a double helix and a homologous strand. The strands are held in close proximity, allowing the strands to test the match and exchange strands if a match is found.
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Figure 1. RAD51 forms a helical filament enclosing strands of DNA. Here, a single strand of DNA, in pink, and a homologous double helix, in orange, enter at the top and exchange strands. It is currently thought that a triple helix is formed inside the RAD51 complex. Atomic coordinates for RAD51 were taken from entry 1szp at the Protein Data Bank (http://www.pdb.org).
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As you might imagine, the process of homologous recombination is intimately linked with cancer. If anything goes wrong, the cell is unable to correct errors, which can lead to carcinogenic mutations or rearrangements. The connection between homologous recombination and cancer is apparent in the BRCA2 protein. BRCA2 was discovered through its linkage to familial breast cancers. Mutations in this gene lead to a high risk for breast cancer. BRCA2 is a large protein that interacts with RAD51, assisting in the process of synapsis. Cells with faulty BRCA2 are unable to pair homologous strands and are prone to DNA breakage and odd chromosomal rearrangements.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The author indicates no potential conflicts of interest.
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Figure 2. BRCA2, shown in green, is a large multipart protein. At the top, one part binds to single-stranded DNA. The portion extending to the left is also thought to bind to double-stranded DNA. The DNA-binding portion is connected to eight repeated motifs that bind to RAD51. The final domain is shown schematically at the bottom since a structure has not been obtained. One function of BRCA2 may be to deliver RAD51 to single-stranded portions of the DNA genome, promoting the formation of the RAD51 filament. Atomic coordinates were taken from entries 1miu and 1n0w at the Protein Data Bank.
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ADDITIONAL READING
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1 Flores-Rozas H, Kolodner RD. Links between replication, recombination and genome instability in eukaryotes. Trends Biochem Sci 2000;25:196–200.[CrossRef][Medline]
2 West SC. Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 2003;4:435–445.[CrossRef][Medline]
3 Pellegrini L, Venkitaraman A. Emerging functions of BRCA2 in DNA recombination. Trends Biochem Sci 2004;29:310–316.[CrossRef][Medline]
Received June 9, 2005;
accepted for publication June 9, 2005.
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Learning Objectives
Disclosure of Potential...
