Figure 7.

Niraparib converts the predominantly PARP1-dependent recruitment of PARP2 to direct trapping of PARP2 at the DNA. (A) The panel shows the two modes of PARP2 foci formation. On the right is the PARP1-dependent and PAR-dependent mode. On the left is the PARP1-independent and direct DNA binding mode via the WGR domain. PARP inhibitor, niraparib, suppresses PAR formation and attenuates PARP1-dependent PARP2 foci, while enhancing the PARP1-independent PARP2 foci by trapping PARP2 on DNA. (B)The diagram shows the four scenarios—with or without PARP1 (left and right) and with or without PARP inhibitors (e.g. niraparib, upper row, or lower row). Upper-left: in the presence of PARP1, the majority of PARP2 is recruited to the foci through a PARP1-dependent and PAR-dependent manner via either direct interaction with PAR or via another PAR binding protein. Upper-right: in the absence of PARP1, PARP2 foci intensity is reduced significantly (∼1/4 of the levels of those with PARP1, depicted by one PARP2 icon) and is mediated by direct interaction between the WGR motif of PARP2 and DNA. Lower-right: in PARP1-deficient cells, PARP inhibitor (niraparib) traps PARP2 at the DNA damage sites to form strong foci (depicted by 5 PARP2 icons). Lower-left: in PARP inhibitor-treated cells with PARP1, the overall intensity of PARP2 foci does NOT change (still 4 PARP2 icons). But they are now primarily made up of direct interaction between PARP2 and DNA since little or no PAR is there. In this case, PARP1 might be continuously recruited and compete with PARP2 for DNA binding.