Changes to the TDP-43 and FUS Interactomes Induced by DNA Damage

Abstract

The RNA-binding proteins TDP-43 and FUS are tied as the thirdleading known genetic cause for amyotrophic lateral sclerosis (ALS), and TDP-43proteopathies are found in nearly all ALS patients. Both the natural function andcontribution to pathology for TDP-43 remain unclear. The intersection offunctions between TDP-43 and FUS can focus attention for those natural functionsmostly likely to be relevant to disease. Here, we compare the role played by TDP-43 and FUS, maintaining chromatin stability for dividing HEK293T cells. We alsodetermine and compare the interactomes of TDP-43 and FUS, quantitatingchanges in those before and after DNA damage. Finally, selected interactions withknown importance to DNA damage repair were validated by co-immunoprecipi-tation assays. This study uncovered TDP-43 and FUS binding to several factorsimportant to DNA repair mechanisms that can be replication-dependent,-independent, or both. These results provide further evidence that TDP-43 has an important role in DNA stability andprovide new ways that TDP-43 can bind to the machinery that guards DNA integrity in cells.