Automodification switches PARP-1 function from chromatin architectural protein to histone chaperone

Abstract

Poly [ADP-ribose] polymerase 1 (PARP-1) is a highly abundant chromatin-associated enzyme. It catalyzes the NAD + -dependent polymerization of long chains of poly-ADP ribose (PAR) onto itself in response to DNA damage and other cues. More recently, the enzymatic activity of PARP-1 has also been implicated in the regulation of gene expression. The molecular basis for the functional switch from chromatin architectural protein to transcription factor and DNA damage responder, triggered by PARP-1 automodification, is unknown. Here, we show that unmodified PARP-1 engages in at least two highaffinity binding modes with chromatin, one of which does not involve free DNA ends, consistent with its role as a chromatin architectural protein. Automodification reduces PARP-1 affinity for intact chromatin but not for nucleosomes with exposed DNA ends. Automodified (AM) PARP-1 has the ability to sequester histones (both in vitro and in cells) and to assemble nucleosomes efficiently in vitro. This unanticipated nucleosome assembly activity of AM-PARP-1, coupled with the fast turnover of the modification, suggests a model in which DNA damage or transcription events trigger transient histone chaperone activity.

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

“…Elegant work from the Luger lab indicated that PARP-1 had histone chaperone function (58). This action of PARP-1, in principle, could modulate ABCA1 expression by facilitating a less open and more repressive chromatin state that precluded LXR binding.…”

Assessment of PARP protein expression in epithelial ovarian cancer by ELISA pharmacodynamic assay and immunohistochemistry

“…In our study, there was no association between NACT and PARP-1 IHC staining, but this may of course be due to a smaller sample size in our study or to differences in the antibodies used. In our study, we used an antibody recognizing highly conserved PARP-1 C-terminus containing the catalytic domain [41] instead of N-terminal domain [26]. As discussed before, the weakness of PARP-1 IHC seems to associate with its dependency on researcherrelated methodological factors such as the antibody used, staining protocol and data analysis.…”

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

“…PARP-1 binds to nucleosomes by recognizing specific structural features (Kim et al 2004) and can alter nucleosome structure while binding cooperatively with transcription factors, such as the pioneer transcription factor Sox2 (Liu and Kraus 2017). Finally, PARP-1 can also function as a histone chaperone by directly binding or recruiting other factors to facilitate nucleosome assembly (Muthurajan et al 2014).…”