DNA double-strand break processing: the beginning of the end

Abstract

Nucleolytic processing of DNA double-strand breaks (DSBs) generates 3' ssDNA tails that are essential for the assembly of DNA damage checkpoint signaling and DNA repair protein complexes. Genetic studies have provided evidence that multiple nuclease activities are involved in DSB end resection. Three recent studies, including work by Jackson and colleagues (pp. 2767- 2772) in the October 15, 2008, issue of Genes & Development, have begun to shed some light on the intricacy of this process.

Figure 1.

DSB end resection in checkpoint signaling and presynaptic filament assembly. DSBs are processed nucleolytically to expose 3′ ssDNA tails that are immediately bound by RPA. The RPA-coated ssDNA recruits the ATR–ATRIP complex, leading to the activation of ATR and downstream effectors such as Chk1 to initiate the checkpoint signaling cascade. For HR repair to occur, RPA is dislodged from the ssDNA and replaced by Rad51 with the assistance of recombination mediator proteins, such as BRCA2, to form the presynaptic filament.

Figure 2.

Model for 5′ DSB end resection pathways in yeast. The MRX–Sae2 ensemble first engages the DSB ends and catalyzes limited end resection. The 3′-tailed intermediate is rapidly processed through the coordinated helicase and nuclease activities of Sgs1 and Exo1 or Dna2, or by the 5′-to-3′ exonucleolytic activity of Exo1, to expose long 3′ ssDNA tracts.