Figure 2: Formation and resolution of TOP2-mediated DSB ends. Proteasome recruitment to a persistent TOP2 cleavable complex results in digestion of covalently linked TOP2 to a short peptide, which can be removed by TDP2 to leave cohesive ligatable ends that can be accurately rejoined by NHEJ. Alternatively, CtIP-dependent endonucleolytic cleavage, perhaps catalyzed by MRE11 in its complex with RAD50 and NBS1 (MRN), can lead to either error-prone NHEJ of the resulting noncohesive ends or to 5′→3′ resection by exonuclease 1, culminating in HRR.