Perlman syndrome nuclease DIS3L2 controlscytoplasmic non-coding RNAs and providessurveillance pathway for maturing snRNAs
2016
The exosome-independent exoribonuclease DIS3L2
is mutated in Perlman syndrome. Here, we used extensive
global transcriptomic and targeted biochemical
analyses to identify novel DIS3L2 substrates in
human cells. We show that DIS3L2 regulates pol
II transcripts, comprising selected canonical and
histone-coding mRNAs, and a novel FTL short RNA
from the ferritin mRNA 5� UTR. Importantly, DIS3L2
contributes to surveillance of maturing snRNAs during
their cytoplasmic processing. Among pol III transcripts,
DIS3L2 particularly targets vault and Y RNAs
and an Alu-like element BC200 RNA, but not Alu repeats,
which are removed by exosome-associated
DIS3. Using 3� RACE-Seq, we demonstrate that
all novel DIS3L2 substrates are uridylated in vivo
by TUT4/TUT7 poly(U) polymerases. Uridylationdependent
DIS3L2-mediated decay can be recapitulated
in vitro, thus reinforcing the tight cooperation
between DIS3L2 and TUTases. Together these results
indicate that catalytically inactive DIS3L2, characteristic
of Perlman syndrome, can lead to deregulation
of its target RNAs to disturb transcriptome homeostasis.
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