fig2

Figure 2. F10 and CPTs both form Top1cc but have different outcomes in response to PARP1/TDP1-mediated repair. A: CPTs form ternary Top1cc that are repaired thru proteasomal degradation to a peptide stub, TDP1-mediated cleavage of the peptide: DNA bond, and PNKP-mediated modulation of 5’-end-phosphorylation status followed by ligation to restore the duplex. In contrast, this same enzymatic process retains FdU in DNA and is susceptible to further Top1cc formation at the same site; B: Activation of homologous HRR due to incomplete TDP1-mediated repair stimulates DNA resection and re-synthesis, which under thymineless conditions increases FdUTP incorporation into DNA, stimulating further Top1-mediated DNA damage; C: In DT40 cells, F10 and CPTs display opposite dependence on TDP1 and PARP1 expression^[53]. CPT: camptothecin; Top1: topoisomerase 1; HRR: recombination repair; TDP1: tyrosyl DNA phosphodiesterase 1; TS: thymidylate synthase; Top1cc: Top1 cleavage complex