PARP1 hyperactivation: mechanisms and cellular consequences.

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is a key DNA-damage sensor that promotes DNA repair by synthesizing poly(ADP-ribose) (PAR), which recruits repair factors, chromatin regulators, and other PAR-binding proteins to DNA lesions. Because PAR shares structural features with RNA, it can engage RNA-binding domains and compete with RNA for common binding surfaces, extending PARP1 signaling beyond DNA repair to regulate RNA-binding proteins (RBPs) and RNA biogenesis. Here, we discuss the mechanisms that drive PARP1 hyperactivation and highlight how excessive PAR synthesis disrupts RNA metabolism, biomolecular condensation, and protein synthesis. Although PARP1 responds to a broad range of DNA damage, the magnitude of its activation is determined by lesion identity rather than overall DNA damage levels. Mechanistically, distinct forms of genotoxic stress, including alkylation, oxidative stress, and ATR inhibition, converge on the generation of abasic sites that APE1 cleaves during base excision repair, producing DNA breaks with 5'-deoxyribose phosphate termini that hyperactivate PARP1. High PAR levels disrupt RBP-RNA interactions, impair RNA export and splicing, and promote aberrant nuclear condensate formation, depleting cytoplasmic mRNA and suppressing translation. In parallel, sustained PARP1 hyperactivation can drive NAD+ and ATP depletion and promote parthanatos, a PARP1-dependent form of regulated cell death implicated in neurodegenerative diseases.

Abstract as supplied by the indexing source. © the authors / publisher.