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Therapeutics

A positive defect

Nature Reviews Cancer volume 5, page 333 (2005)Cite this article

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Stephen West and colleagues investigated the interaction between BRCA2 and RAD51. RAD51 is a crucial component of the homologous recombination (HR) repair pathway and interacts with BRCA2 through the BRCA2 BRC-repeat motifs and through an interaction domain in the carboxyl terminus. Current data indicate that this interaction facilitates two essential processes: the formation of RAD51 nucleoprotein filaments, which are essential for RAD51 recombinase activity, and the rapid association of RAD51 with sites of DNA damage. West and colleagues used a series of tagged protein fragments from the C-terminus of BRCA2 to determine the RAD51-interaction motif. They found that phosphorylation of Ser3291 in the C-terminus of BRCA2 regulates the interaction with RAD51. Phosphorylation of this residue is carried out by cyclin-dependent kinases (CDKs) in the G2/M phase of the cell cycle. Furthermore, CDK-dependent phosphorylation was inhibited after DNA damage, facilitating the interaction between RAD51 and the BRCA2 C-terminus and the localization of RAD51 to DNA-damage foci. These findings indicate that BRCA2 Ser3291 phosphorylation regulates the activity of RAD51, preventing its recombinase activity during G2/M but facilitating the repair of any replication-induced strand breaks during S-phase.

Importantly, evidence from human breast cancers indicates that the region around Ser3291 is a mutational hot spot. Loss of the C-terminal portion of BRCA2, but retention of the BRC domains, results in an impaired response to ionizing radiation — RAD51-focus formation is lost and repair of DNA damage through HR is disrupted. Although the isolation of this phosphorylation site might indicate potential strategies for therapeutic intervention, two other papers indicate that tumours that lack BRCA2 (or BRCA1) can be targeted precisely because they cannot carry out HR effectively.

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ORIGINAL RESEARCH PAPERS

  1. Esashi, F. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinatorial repair. Nature 434, 598–604 (2005)

    Article  CAS  Google Scholar 

  2. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymerase. Nature 434, 913–917 (2005)

    Article  CAS  Google Scholar 

  3. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a novel therapeutic strategy. Nature 434, 917–921 (2005)

    Article  CAS  Google Scholar 

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Authors
  1. Nicola McCarthy
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McCarthy, N. A positive defect. Nat Rev Cancer 5, 333 (2005). https://doi.org/10.1038/nrc1618

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