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Science. 2017 May 26;356(6340):859-862. doi: 10.1126/science.aai9372.

Tudor-SN-mediated endonucleolytic decay of human cell microRNAs promotes G1/S phase transition.

Author information

1
Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
2
Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA.
3
Genomics Research Center, University of Rochester, Rochester, NY 14642, USA.
4
Office of Advanced Research Computing, Rutgers University, Piscataway, NJ 08854, USA.
5
Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
6
Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA. lynne_maquat@urmc.rochester.edu.
7
Department of Oncology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression. The pathways that mediate mature miRNA decay are less well understood than those that mediate miRNA biogenesis. We found that functional miRNAs are degraded in human cells by the endonuclease Tudor-SN (TSN). In vitro, recombinant TSN initiated the decay of both protein-free and Argonaute 2-loaded miRNAs via endonucleolytic cleavage at CA and UA dinucleotides, preferentially at scissile bonds located more than five nucleotides away from miRNA ends. Cellular targets of TSN-mediated decay defined using microRNA sequencing followed this rule. Inhibiting TSN-mediated miRNA decay by CRISPR-Cas9 knockout of TSN inhibited cell cycle progression by up-regulating a cohort of miRNAs that down-regulates mRNAs that encode proteins critical for the G1-to-S phase transition. Our study indicates that targeting TSN nuclease activity could inhibit pathological cell proliferation.

PMID:
28546213
PMCID:
PMC5551500
DOI:
10.1126/science.aai9372
[Indexed for MEDLINE]
Free PMC Article

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