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

The RNA-binding proteins TDP-43 and FUS are tied as the
third leading
known genetic cause for amyotrophic lateral sclerosis (ALS), and TDP-43
proteopathies are found in nearly all ALS patients. Both the natural
function and contribution to pathology for TDP-43 remain unclear.
The intersection of functions between TDP-43 and FUS can focus attention
for those natural functions mostly 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 also determine and compare
the interactomes of TDP-43 and FUS, quantitating changes in those
before and after DNA damage. Finally, selected interactions with known
importance to DNA damage repair were validated by co-immunoprecipitation
assays. This study uncovered TDP-43 and FUS binding to several factors
important 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 and provide new ways
that TDP-43 can bind to the machinery that guards DNA integrity in
cells.