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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.

Original publication

DOI

10.1083/jcb.201612131

Type

Journal article

Journal

J Cell Biol

Publication Date

07/08/2017

Volume

216

Pages

2373 - 2389

Keywords

A549 Cells, Animals, Argonaute Proteins, Cell Nucleus, DEAD-box RNA Helicases, DNA Breaks, Double-Stranded, DNA Repair, HEK293 Cells, Humans, Mice, Nuclear Proteins, Nucleic Acid Conformation, Phosphorylation, RNA Interference, RNA, Double-Stranded, Ribonuclease III, Signal Transduction, Time Factors, Trans-Activators, Transfection, Tumor Suppressor p53-Binding Protein 1