Figure 7 | Oncogene

Figure 7

From: NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699

Figure 7

PAR is essential for DNA damage activated NF-κB. (a) DNA damage, such as IR, activates PARP-1, recruiting it to the site of damaged DNA. This results in formation of the negatively charged PAR polymer. The NF-κB p65-p50 heterodimer is also translocated to the nucleus following DNA damage via activation of the canonical pathway of NF-κB activation. When in proximity to regions with overall negative charge, such as that of the PAR polymer, a conformational change in p65 can be induced, exposing the positively charged DNA-binding interface of p65. Thus, we propose that it is this negative charge on the PAR polymer that is attracting p65 to DNA bind, (as PARP-1 and the polymer are recruited to sites of damaged DNA), upregulating transcription of NF-κB-dependent genes, protecting against apoptosis and conferring radio-resistance. (b) When the PARP inhibitor, AG-014699 is present, PARP-1 is no longer active and cannot form the polymer. Hence in this case, we see reduced DNA binding and transcriptional activation following IR, with induction of apoptosis and ultimately radio-sensitization.

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