Regulatory apoptotic fragment of PARP1 complements catalytic fragment for PAR and DNA-dependent activity but inhibits DNA-induced catalytic stimulation of PARP2.

To maintain tissue homeostasis, cell proliferation is balanced by cell death. PARP1 is an important protein involved in both processes. Upon sensing DNA damage, PARP1 forms poly(ADP-ribose) (PAR) chains to recruit the repair proteins, ensuring genome integrity and faithful cell proliferation. In addition, PAR also regulates the activity of PARP1. Persistent DNA damage can signal the cell to progress toward programmed cell death, apoptosis. During apoptosis, proteolytic cleavage of PARP1 generates an N-terminal, ZnF1-2 (DNA binding or regulatory fragment), and C-terminal, PARP1 (catalytic or PAR carrier fragment), which exhibits a basal activity. Regulation of the apoptotic fragments by PAR has not been studied. Here, we report that PAR inhibits the basal level activity of PARP1 and ZnF1-2 interacts with PARP1 to exhibit DNA-dependent stimulation and partially restores the PAR-dependent stimulation. Interestingly, along with the auto-modification domain of PARP1, the DNA-binding domains, ZnF1-2, also acts as an acceptor of PARylation; therefore, ZnF1-2 exhibits a reduced affinity for DNA upon PARylation. Furthermore, we show that ZnF1-2 shows trans-dominant inhibition of DNA-dependent stimulation of PARP2. Altogether, our study explores the regulation of the catalytic activity of PARP1 and PARP2 by the regulatory apoptotic fragment of PARP1.