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A Role for Small RNAs in DNA Double-Strand Break Repair

ABSTRACT: Here we identify a novel class of small RNAs that are ~21-nucleotide in length and are produced from the sequences in the vicinity of DNA double strand break (DSB) sites in Arabidopsis and humans. We named them diRNAs for DSB-induced small RNAs. In Arabidopsis, the biogenesis of diRNAs requires the PI3 kinase ATR, RNA polymerase IV (Pol IV), and Dicer-like proteins. Mutations in these proteins as well as in Pol V cause significant reduction in DSB repair efficiency. diRNAs are recruited by Argonaute 2 (AGO2) to mediate DSB repair. In humans, knocking down Dicer or Ago2 causes a significant reduction in DSB repair. Our findings reveal a novel biological function for small RNAs in the DSB repair pathway. We propose that diRNAs may function as guide molecules for chromatin modifications or recruitment of repair complexes at DSB sites to facilitate repair.

ORGANISM(S): Arabidopsis thaliana Homo sapiens

PROVIDER: GSE36338 | GEO | 2012/03/27

SECONDARY ACCESSION(S): PRJNA153297

REPOSITORIES: GEO

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A Role for Small RNAs in DNA Double-Strand Break Repair

Project description:Here we identify a novel class of small RNAs that are ~21-nucleotide in length and are produced from the sequences in the vicinity of DNA double strand break (DSB) sites in Arabidopsis and humans. We named them diRNAs for DSB-induced small RNAs. In Arabidopsis, the biogenesis of diRNAs requires the PI3 kinase ATR, RNA polymerase IV (Pol IV), and Dicer-like proteins. Mutations in these proteins as well as in Pol V cause significant reduction in DSB repair efficiency. diRNAs are recruited by Argonaute 2 (AGO2) to mediate DSB repair. In humans, knocking down Dicer or Ago2 causes a significant reduction in DSB repair. Our findings reveal a novel biological function for small RNAs in the DSB repair pathway. We propose that diRNAs may function as guide molecules for chromatin modifications or recruitment of repair complexes at DSB sites to facilitate repair. 28 samples from Arabidopsis thaliana in various genetic backgrounds and 5 samples from the human cells, small RNA sequencing

2012-03-26 | E-GEOD-36338 | biostudies-arrayexpress

IDN2 Interacts with RPA and Facilitates DNA Double-Strand Break Repair by Homologous Recombination in Arabidopsis

Project description:Repair of DNA double-strand break (DSB) is critical for the maintenance of genome integrity. We have previously shown that a class of DSB-induced small RNAs (diRNAs) facilitates homologous recombination (HR)-mediated DSB repair in Arabidopsis thaliana. Here we show that INVOLVED IN DE NOVO 2 (IDN2), a double-stranded RNA (dsRNA) binding protein involved in small RNA-directed DNA methylation, is required for DSB repair in Arabidopsis. We find that IDN2 interacts with the heterotrimeric replication protein A (RPA) complex. Depletion of IDN2 or the diRNA-binding ARGONAUTE 2 (AGO2) leads to increased accumulation of RPA at DSB sites and mislocalization of the recombination factor RAD51. These findings support a model in which IDN2 interacts with RPA and facilitates the release of RPA from ssDNA tails and subsequent recruitment of RAD51 at DSB sites to promote DSB repair.

2017-02-28 | GSE94305 | GEO

A small RNA response to DNA ends in Drosophila

Project description:Small RNAs have been implicated in numerous cellular processes, including effects on chromatin structure and the repression of transposons. We describe the generation of a small RNA response at DNA ends in Drosophila that is analogous to the recently reported DSB-induced RNAs (diRNAs) or Dicer and Drosha dependent small RNAs (ddRNAs) in Arabidopsis and vertebrates. Active transcription in the vicinity of the break amplifies this small RNA response, demonstrating that the normal mRNA contributes to the endo-siRNA precursor. The double-stranded RNA precursor forms with an antisense transcript that initiates at the DNA break. Breaks are thus sites of transcription initiation, a novel aspect of the cellular DSB response. This response is specific to a double-strand break since nicked DNA structures do not trigger small RNA production. The small RNAs are generated independently of the exact end structure (blunt, 3'- or 5'-overhang), can repress homologous sequences in trans and may therefore - in addition to putative roles in repair - exert a quality control function by clearing potentially truncated messages from genes in the vicinity of the break.

2012-08-03 | GSE38967 | GEO

A small RNA response to DNA ends in Drosophila

2012-08-03 | E-GEOD-38967 | biostudies-arrayexpress

Effects of the RNA Exosome on damage induced small RNAs in the 28S ribosomal locus

Project description:The repair of DNA double strand breaks (DSBs) has recently been shown to depend not only on protein function but also on RNA. In particular, the processing of a long damage-induced RNA into small damage induced RNAs (diRNAs) has been a focus of interest. Given that the RNA exosome has been shown in Drosophila and human cells to participate in DSB repair, we investigated whether the catalytic components EXOSC10 and DIS3 have a function in diRNA biogenesis in human cells.

2019-04-10 | GSE113109 | GEO

Next-generation sequencing reveals two populations of damage-induced small RNAs at endogenous DNA double-strand breaks

Project description:Recent studies suggest that the repair of DNA double-strand breaks (DSBs) is supported by damage-induced small RNAs (diRNAs) that are generated by Drosha and Dicer from transcripts that originate from the regions flanking the break. However, transcription and diRNA production at naturally occurring DSBs in mammalian genomes remain controversial. We have used the homing endonuclease I-PpoI to produce DSBs in human and mouse cells, and we have analyzed the biogenesis of diRNAs at I-PpoI induced breaks in the 28S rDNA and the Ryr2 gene. We provide direct evidence that RNA polymerase II transcribes the sequences that flank the DSBs. Our results also reveal that the resulting transcripts are processed into two types of diRNAs with characteristic length and terminal nucleotide signatures. Furthermore, diRNA production is independent of Drosha and DGCR8, and only a subset of diRNAs depends on Dicer, as shown by small RNA analyses of knock-out cells that lack specific RNA processing enzymes. Our findings are compatible with previous observations of a general transcription inhibition at DSBs and provide novel insights into the mechanisms of RNA synthesis and processing at DSBs.

2018-10-22 | GSE106764 | GEO

High-throughput sequencing of Pol IV and RDR2 transcripts, and their DCL3-diced products, generated from an M13mp18 (+) strand DNA template

Project description:In plants, the biogenesis of 24 nt and 23 nt small interfering RNAs (siRNAs) requires NUCLEAR RNA POLYMERASE IV (Pol IV), RNA-DEPENDENT RNA POLYMERASE 2 (RDR2) and DICER-LIKE 3 (DCL3). We show that single-stranded M13 bacteriophage DNA can be used as a template for siRNA synthesis in vitro. Deep sequencing of RNAs produced from the in vitro reactions of Pol IV, RDR2 and DCL3 shows that Pol IV transcribes the DNA into first-strand RNAs which RDR2 then uses as templates to synthesize complementary second strands. These siRNA precursor transcripts made by Pol IV and RDR2 are mostly 30-50 nt. An untemplated 3' terminal nucleotide is a characteristic of RDR2 transcripts. DCL3 dicing of double-stranded precursor RNAs synthesized by Pol IV and RDR2 generates siRNAs that are mostly 24 nt, with a smaller population of 23 nt also produced.

2019-07-01 | GSE126086 | GEO

Argonaute 2 binds directly to tRNA genes and promotes gene repression in cis

Project description:To further our understanding of the RNAi machinery within the human nucleus, we analyzed the chromatin and RNA binding of Argonaute 2 (AGO2) within human cancer cell lines. Our data indicated that AGO2 binds directly to nascent tRNA and 5S rRNA, and to the genomic loci from which these RNAs are transcribed, in a small RNA- and DICER-independent manner. AGO2 chromatin binding was not observed at non-TFIIIC-dependent RNA polymerase (Pol) III genes or at extra-TFIIIC (ETC) sites, indicating that the interaction is specific for TFIIIC-dependent Pol III genes. A genome-wide analysis indicated that loss of AGO2 caused a global increase in the mRNA expression level among genes that flank AGO2-bound tRNA genes. This effect was shown to be distinct from that of the disruption of DICER, DROSHA, or CTCF. We propose that AGO2 binding to tRNA genes has a novel and important regulatory role in human cells.

2015-05-17 | GSE68813 | GEO

Argonaute 2 binds directly to tRNA genes and promotes gene repression in cis

2015-05-17 | E-GEOD-68813 | biostudies-arrayexpress

Ago2 or Dicer knockdown effects on mRNA levels in HeLa

Project description:Analysis of mRNA changes in HeLa cells following Ago2 or Dicer depletion. Dicer, a cytoplasmic RNase III, generates the mature form of small RNAs including microRNA. Ago2 is a component of an effector complex of microRNA. Keywords: gene expression array-based (RNA / in situ oligonucleotide)

2009-02-05 | GSE13638 | GEO

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