Dicer Promotes Transcription Termination at Sites of Replication Stress to Maintain Genome Stability

Abstract

Nuclear RNA interference is an important regulator of transcription and epigenetic modification, but the underlying mechanisms remain elusive. Using a genome-wide approach in the fission yeast S. pombe we have found that Dcr1, but not other components of the canonical RNAi pathway, promotes the release of Pol II from the 3’ end of highly transcribed genes, and, surprisingly, from antisense transcription of rRNA and tRNA genes, which are normally transcribed by Pol I and Pol III. These Dcr1-terminated loci correspond to sites of replication stress and DNA damage, likely resulting from transcription-replication collisions. At the rDNA loci, release of Pol II facilitates DNA replication and prevents homologous recombination, which would otherwise lead to loss of rDNA repeats especially during meiosis. Our results reveal a novel role for Dcr1-mediated transcription termination in genome maintenance and may account for widespread regulation of genome stability by nuclear RNAi in higher eukaryotes.

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

“…The endoribonuclease Dicer shares similarities with the majority of caretaker genes in that it cannot initiate tumors de novo, as illustrated here by the absence of medulloblastoma in Atoh1-Cre;Dicer1flox/flox mice. Furthermore, the endoribonuclease Dicer has recently been shown to maintain genomic stability in Schizosaccharomyces pombe by promoting transcription termination at sites associated with replication stress and DNA damage (Castel et al 2014). This is likely to occur in higher eukaryotes.…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…In addition, human Dicer has been shown to associate with the chromatin structures of ribosomal DNA [124] . It also has a role in termination of transcription [126] , in regulation of intergenic transcription in the human β-globin gene cluster [127] and in regulation of nuclear receptor (NR) signaling, as evidenced by direct binding of Dicer to NR promoter regions [128] . Further, Dicer has been reported to be required in heterochromatin formation in fission yeast [129] and in vertebrates [130] , suggesting its presence in the nucleus of human cells could be due to an as yet unidentified role in mammalian TGS ( Figure 2B).…”

Small RNA-mediated regulation of DNA dosage in the ciliate Oxytricha

“…More recently, studies in S. pombe reported that Dcr-1 plays an important role in maintenance of genome integrity by inhibiting DNA recombination at rDNA repeats (Castel et al 2014). Furthermore, Dicer in S. pombe maintains genomic integrity at rDNA loci by promoting transcription termination (Castel et al 2014). Oxytricha dcl-1 mutants show 3.3-fold reduced levels in small RNAs that map to the rDNA chromosome and a twofold reduction in rDNA copy number.…”

“…In Neurospora, DNA damage induces expression of Argonaute QDE-2 interacting small RNAs (qiRNAs) and an increase in ribosomal RNA levels ); however, it is unknown whether the ribosomal DNA (rDNA) copy number is influenced as well. More recently, studies in S. pombe reported that Dcr-1 plays an important role in maintenance of genome integrity by inhibiting DNA recombination at rDNA repeats (Castel et al 2014). Furthermore, Dicer in S. pombe maintains genomic integrity at rDNA loci by promoting transcription termination (Castel et al 2014).…”