Genotoxic stress-induced phase separation by liquid demixing

Genomic lesions have to be shielded from unwanted enzymatic activities, so that repair proteins have time to arrive at the damaged site and take care of the damaged region. One way how this can be achieved is by compartmentalization, i.e. by subdividing the soluble nuclear space and generating a repair compartment around the DNA lesion. Such membrane-less compartmentalization can occur by liquid demixing of soluble components, culminating in a liquid-liquid phase separation. We recently discovered that poly(ADP-ribose), a nucleic acid-like molecule generated at genomic lesions, assembles multiple proteins with low complexity domains and that this triggers their dynamic phase separation. Current work in the lab aims at characterizing the physicochemical principles of PAR-seeded phase separations and at elucidating their functions for genome integrity maintenance.


Further reading:

Aguzzi & Altmeyer
Phase separation: linking cellular compartmentalization to disease
Trends Cell Biol. 2016 Jul;26(7):547-558.

Teloni & Altmeyer
Readers of poly(ADP-ribose): designed to be fit for purpose
Nucl Acids Res. 2015 Dec 15; pii:gkv1383

Altmeyer et al.
Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)
Nature Comm. 2015 Aug 19;6:8088

Kilic et al.
Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments
EMBO J. 2019 Aug 15;38(16):e101379.