02 September 2015

Novel model for PAR-induced dynamic reorganization of the nucleus around sites of DNA damage

An international team of researchers led by Jiri Lukas and Matthias Altmeyer from Novo Nordisk Foundation Center for Protein Research introduces a novel role for poly(ADP-ribose) (PAR) as organizer of subcellular architecture providing cells with an opportunity to filter protein interactions occurring on damaged chromatin.

Intrinsically disordered proteins containing prion-like low complexity domains (LCD) undergo spontaneous self-assembly to generate higher-order structures. The initial kinetics during the nucleation phase of this process is relatively slow due to fast reverse reaction rates. However, molecular seeds can significantly accelerate the nucleation process and help overcome the kinetic barrier and drive the formation of higher-order structures.

In their study published in August in Nature Communications, Altmeyer, Lukas and co-workers propose that the anionic biopolymer PAR is one such molecular seed for the self-assembly of LCD-containing proteins. By virtue of its charge, PAR can trap intrinsically disordered LCD-containing proteins and trigger their dynamic assembly into higher-order structures. Under physiological conditions, the PAR-seeded assembly of LCD-containing proteins thus represents a liquid-liquid phase separation, with the potential to dynamically compartmentalize the subcellular space.

To explore their discovery in a physiologically relevant context, the team chose cellular response to DNA damage, which is known to involve massive and locally confined spikes of PAR levels due to hyperactivation of PARP enzymes at DNA break sites. Indeed, the authors were able to show that this entails increased local concentration of LCD-containing proteins accompanied by rapid phase separation and liquid demixing directly at the sites of DNA damage, providing cells with an opportunity to filter early protein interactions occurring on damaged chromatin.

Title: Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

Authors: Matthias Altmeyer, Kai J. Neelsen, Federico Teloni, Irina Pozdnyakova, Stefania Pellegrino, Merete Grøfte, Maj-Britt Druedahl Rask, Werner Streicher, Stephanie Jungmichel, Michael Lund Nielsen & Jiri Lukas

Published in Nature Communications 6, Article number 8088 (doi:10.1038/ncomms9088).  Follow this link to read the paper at the Nature Communications web site.

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen. The center is supported financially by the Novo Nordisk Foundation (Grant agreement NNF14CC0001).