Poly(ADP-ribose) polymerase 1-mediated ADP-ribosylation sites (Glu/Asp-PARylation sites)

The Glutamate/Aspartate side-chain carboxyl groups on PARP1-dependent DNA damage response proteins are the biochemical sites for the covalent attachment of poly(ADP-ribose) (PAR) polymers. This post-translational modification, catalyzed by Poly(ADP-ribose) polymerase 1 (PARP1) using NAD+ as a substrate, occurs rapidly in response to DNA single-strand breaks (Gibson & Kraus, 2012). The addition of negatively charged PAR chains to these carboxyl groups on histones and other repair proteins promotes chromatin relaxation and recruits essential DNA repair factors like XRCC1 to the lesion (Lord & Ashworth, 2017). While recent evidence suggests that serine residues are the predominant modification sites when the cofactor HPF1 is present, the modification of glutamate and aspartate residues remains a key aspect of PARP-mediated signaling (Palazzo et al., 2018). Therapeutic agents known as PARP inhibitors target the PARP1 enzyme itself, effectively preventing the modification of these carboxyl groups and leading to the accumulation of unrepaired DNA damage, which is lethal to cancer cells with pre-existing repair deficiencies (Suskiewicz et al., 2020).

Other names

Glutamate/Aspartate side-chain carboxyl groups on PARP1-dependent DNA damage response proteinsADP-ribose acceptor sitesPARP1 substrate modification sitesGlu/Asp-linked ADP-ribosylation

PARP inhibitors competitively inhibit the binding of NAD+ to the PARP1 enzyme, thereby preventing the covalent attachment of ADP-ribose units to the side-chain carboxyl groups of glutamate and aspartate residues on target proteins (Gibson & Kraus, 2012; Lord & Ashworth, 2017).