PARP1 Exhibits an Enzymatically Inactive Chromatin Binding Mode

Abstract

Poly (ADP-ribose) Polymerase 1 (PARP1) is an abundant nuclear enzyme that dynamically engages chromatin in diverse cellular scenarios. In the context of DNA repair, PARP1 becomes enzymatically activated and subsequently attaches ADP-ribose units onto various proteins, including histones, to signal and coordinate the DNA damage response. In the absence of DNA damage, PARP1 modulates chromatin structure by directly binding to nucleosomes, however, the molecular basis of this interaction is unknown. Here, we define a distinct, enzymatically inactive mode of PARP1 chromatin binding, in which the Zn1, Zn2, Zn3, and BRCT domains cooperatively bind nucleosomal linker DNA and drive compaction of undamaged chromatin. This binding mode does not trigger catalytic activation and therefore is insensitive to PARP inhibitors (PARPi). Together, our results support a model in which PARP1 associates with the genome in an inactive state to compact chromatin and to surveil for DNA lesions. SummaryPARP1 engages undamaged chromatin in a distinct binding mode that results in chromatin compaction but does not lead to enzymatic activation.