Abstract
The endoribonuclease Dicer is a key component of the human RNA interference pathway and is known for its role in cytoplasmic microRNA production. Recent findings suggest that noncanonical Dicer generates small noncoding RNA to mediate the DNA damage response (DDR). Here, we show that human Dicer is phosphorylated in the platform-Piwi/Argonaute/Zwille-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks. We further demonstrate that turnover of damage-induced nuclear, double-stranded (ds) RNA requires additional phosphorylation of carboxy-terminal Dicer residues (S1728 and S1852). DNA damage-induced nuclear Dicer accumulation is conserved in mammals. Dicer depletion causes endogenous DNA damage and delays the DDR by impaired recruitment of repair factors MDC1 and 53BP1. Collectively, we place Dicer within the context of the DDR by demonstrating a DNA damage-inducible phosphoswitch that causes localized processing of nuclear dsRNA by p-Dicer to promote DNA repair.
Highlights
The endoribonuclease Dicer is a key component of the RNAi pathway
We showed previously that human Dicer localizes to the nucleus to process endogenous-dsRNA derived from overlapping transcription units
The tumor suppressor p53 is an integral component of the DNA damage response (DDR) and has recently been shown to stimulate Dicer expression via the p53 family member TAp63
Summary
The endoribonuclease Dicer is a key component of the RNAi pathway. Dicer processing generates 20–25-nt-long miRNA from a stem-loop precursor miRNA (Chendrimada et al, 2005; Haase et al, 2005). Mature miRNA are loaded onto the Argonaute-containing, RNA-induced silencing complex to target complementary mRNA for degradation or inhibition of translation (Filipowicz et al, 2008; Meister, 2013; Ha and Kim, 2014). Human Dicer recognizes additional double-stranded (ds)RNA species, such as pre-mRNA, tRNA, and long noncoding RNA (Rybak-Wolf et al, 2014). Dicer processes a subset of RNA polymerase II (RNAPII)-dependent, noncanonical miRNA precursors, which are termed transcription start site miRNA (Zamudio et al, 2014)
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