Abstract
Recently, it was reported that knockdown of DICER reduced the ATM-dependent DNA damage response and homologous recombination repair (HRR) via decreasing DICER-generated small RNAs at the damage sites. However, we found that knockdown of DICER dramatically increased cell resistance to camptothecin that induced damage required ATM to facilitate HRR. This phenotype is due to a prolonged G1/S transition via decreasing DICER-dependent biogenesis of miRNA let-7, which increased the p21Waf1/Cip1/p27Kip1 levels and resulted in decreasing the HRR efficiency. These results uncover a novel function of DICER in regulating the cell cycle through miRNA biogenesis, thus affecting cell response to DNA damage.
Highlights
MicroRNAs are ∼22 nucleotide small RNAs that regulate mRNA expression through binding to the 3 untranslated region (3 UTR) of their target mRNAs
It was reported that the DICER-generated small RNA products at the DNA double-strand break (DSB) sites [20] were required for the ATM-dependent DNA damage response [21] and efficient homologous recombination repair (HRR) [22,23], which was independent of miRNA biogenesis
Through exploring the underlying mechanism, we discovered that knockdown of DICER affecting cell response to DNA damage is independent of the small RNAs but depends on biogenesis reduction of let-7, which results in overexpression of p21Waf1/Cip1/p27Kip1 and prolonged G1/S transition
Summary
MicroRNAs (miRNAs) are ∼22 nucleotide small RNAs that regulate mRNA expression through binding to the 3 untranslated region (3 UTR) of their target mRNAs. The reports that DICER was required for the ATM-dependent DNA damage response [21] and efficient HRR [22,23] suggest that knockdown of DICER should sensitize human cells to DNA DSB inducers, to CPT treatment.
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