The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context

The regulation of repair processes including base excision repair (BER) in the presence of DNA damage is implemented by a cellular signal: poly(ADP-ribosyl)ation (PARylation), which is catalysed by PARP1 and PARP2. Despite ample studies, it is far from clear how BER is regulated by PARPs and how the roles are distributed between the PARPs. Here, we investigated the effects of PARP1, PARP2 and PARylation on activities of the main BER enzymes (APE1, DNA polymerase beta [Pol beta] and DNA ligase III alpha [LigIII alpha]) in combination with BER scaffold protein XRCC1 in the nucleosomal context. We constructed nucleosome core particles with midward- or outward-oriented damage. It was concluded that in most cases, the presence of PARP1 leads to the suppression of the activities of APE1, Pol beta and to a lesser extent LigIII alpha. PARylation by PARP1 attenuated this effect to various degrees depending on the enzyme. PARP2 had an influence predominantly on the last stage of BER: DNA sealing. Nonetheless, PARylation by PARP2 led to Pol beta inhibition and to significant stimulation of LigIII alpha activities in a NAD(+)-dependent manner. On the basis of the obtained and literature data, we suggest a hypothetical model of the contribution of PARP1 and PARP2 to BER.

Automated summary

The study revealed that the presence of PARP1 leads to the suppression of BER enzymes' activities, while PARP2 predominantly influences the last stage of BER. PARylation attenuates the inhibitory effect of PARP1, but results in Pol beta inhibition and significant stimulation of LigIII alpha by PARP2 in a NAD(+)-dependent manner.