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. 2016 Dec 8;36(3):361–373. doi: 10.15252/embj.201592426

Figure 4. Molecular mechanisms for the formation of a DSB by sequential Top1 ribonuclease activity and Top1 cleavage events on the opposite DNA strand from the newly incorporated ribonucleotides.

Figure 4

  1. Ribonucleotides are preferentially incorporated on the leading strand when Pol ε is genetically altered.
  2. Newly incorporated ribonucleotides are normally removed by RER initiated by RNase H2 incision at the ribonucleotide site.
  3. In the absence of RNase H2, Top1 forms a cleavage complex at the ribonucleotide site.
  4. The attack by 2′‐hydroxyl group on the phosphotyrosyl bond releases Top1, converting the ribonucleotides into nicks with 2′,3′‐cyclic phosphate ends (triangle). A detailed biochemical reaction is shown in the box on the right.
  5. Subsequent cleavage by Top1 on the opposite strand of the existing nick leads to a DSB.
  6. The resulting DSB with covalently linked Top1 at the end is prone to religate/recombine with other DNA ends.
  7. Alternatively, homologous recombination (dependent on Rad51 and Rad52) repairs the DSB.