Work

HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase

Year: 2021

Type: article

Abstract: Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, histone PARylation factor (HPF1) was shown to be a critical modulator of the activity of PARP1 by facilitating PARylation of histones and redirecting the target amino acid specificity from acidic to serine residues. Here we investigate the mechanism and specific consequences of HPF1-mediated PARylation using nucleosomes as both activators and substrates for PARP1. HPF1 provides that catalytic base Glu284 to substantially redirect PARylation by PARP1 such that the histones in nucleosomes become the primary recipients of PAR chains. Surprisingly, HPF1 partitions most of the reaction product to free ADPR, resulting in much shorter PAR chains compared to reactions in the absence of HPF1. This HPF1-mediated switch from polymerase to hydrolase has important implications for the PARP1-mediated response to DNA damage and raises interesting new questions about the role of intracellular ADPR and depletion of NAD + .

Source: eLife

DOI: 10.7554/elife.65773

Authors: Johannes Rudolph, Genevieve Roberts, Uma M. Muthurajan, Karolin Luger

Institutions: University of Colorado Boulder, Howard Hughes Medical Institute

Language: English

Topic: PARP inhibition in cancer therapy

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $2,500

Funders: Howard Hughes Medical Institute, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences