PARbinding

PARbinding refers to the interaction between proteins and poly(ADP-ribose) (PAR) polymers or ADP-ribose moieties generated by poly(ADP-ribose) polymerases (PARPs). PAR binding is a key facet of the cellular response to DNA damage and other stress conditions, enabling rapid recruitment and regulation of numerous proteins at damaged sites.

Typical PAR-binding occurs via specific modules or motifs, such as PAR-binding motifs (PBMs) and protein domains including macro domains and WWE domains. These features allow the proteins to recognize and bind PAR chains that are synthesized by PARP enzymes, particularly PARP1, in response to DNA strand breaks. PAR chains are synthesized from NAD+ and can be rapidly degraded by PARG and ARH3, giving PAR signaling a transient nature.

Role in DNA repair: PAR binding helps recruit and organize factors involved in base excision repair, single-strand break repair, and double-strand break repair pathways such as homologous recombination; it also influences chromatin structure and transcription near damage sites. PAR-binding proteins may act as scaffolds, remodelers, or enzymes regulated by PARylation.

Regulation and dynamics: The extent and duration of PAR binding are influenced by PARP activity, availability of NAD+, and degradation by PARG/ARH3. Inhibitors of PARP reduce PAR formation and disrupt PAR-mediated recruitment, a basis for synthetic lethality strategies in BRCA-mutant cancers.

Detection and study: PAR-binding is studied using PAR overlay assays, affinity purification with PAR or PBM-containing peptides, immunoprecipitation with anti-PAR antibodies, and mutational analyses of PBMs or binding domains.

Clinical and research relevance: PARbinding is an active area of research with implications for cancer therapy, aging, and neurodegeneration. Understanding PAR-binding helps elucidate the network of PAR-dependent signaling and may reveal new therapeutic targets.