We conclude that Ku70/80 was upregulated in higher primates to suppress Alu elements from altering mRNA splicing. When Ku is depleted a number of essential genes involved in ribosome biogenesis and mRNA processing are miss-spliced and lost due to NMD, leading to cell death. 6/6

Upon closer inspection, we demonstrate that Ku depletion activates cryptic splice acceptor sites within antisense Alu elements, which are located immediately upstream of a stem loop that Shan Zha’s group recently demonstrated to be bound by Ku70/80. 5/n

Using a Halo-PROTAC ligand we can degrade Halo-Ku70 and Halo-Ku80 and cells rapidly die! At an early timepoint before a substantial amount of cell death occurs, we observed dramatic changes in RNA splicing. Strikingly, antisense Alu elements were significantly enriched in miss-spliced introns. 4/n

Giovanni and Kathy had previously demonstrated that the number of Alu repeats substantially increased in the genomes of higher primates at the exact evolutionary junction at which Ku expression shot through the roof. Could there be a connection between Alu element expansion and Ku expression? 3/n

Ku70/80 is typically thought of as a NHEJ factor that repairs DSBs. However, Ku is essential in human cells, but not in mouse cells. Ku expression is also dramatically increased in higher primates, compared to primitive primates and other mammals. So, what is Ku’s essential function? 2/n

Using a Halo-PROTAC ligand we can rapidly degrade Ku70 and Ku80 and cells rapidly die! At an early timepoint before a substantial amount of cell death occurs, we observed dramatic changes in RNA splicing. Strikingly, antisense Alu elements were dramatically enriched in miss-spliced introns. 4/n

Kathy Meek had previously demonstrated that at the Alu elements content substantially expanded in the genomes of higher primates at the exact evolutionary junction at which Ku expression increased. Could there be a connection between Alu element expansion and Ku expression? 3/n

Ku70/80 is a NHEJ factor that repairs DNA double strand breaks. However, Ku is essential in human cells but not in mouse cells. Ku expression is also dramatically increased in higher primates, compared to primitive primates and other mammals. So, what is Ku’s essential function? 2/n

There is no way they will be able to reschedule before January.

12 ms exposure 250 fps doesn’t math.

Its technically not the correct term. B is simply lethal when A is not around. Text book example would be B creates a toxic metabolite that A gets rid of.

Sounds like isoform B is dominant negative lethal in the absence of isoform A.

16 posts??? TLDR 🤣