Abstract
Multiple myeloma, the second most frequent hematologic tumor after lymphomas, is an incurable cancer. Recent sequencing efforts have identified the ribonuclease DIS3 as one of the most frequently mutated genes in this disease. DIS3 represents the catalytic subunit of the exosome, a macromolecular complex central to the processing, maturation and surveillance of various RNAs. miRNAs are an evolutionarily conserved class of small noncoding RNAs, regulating gene expression at post-transcriptional level. Ribonucleases, including Drosha, Dicer and XRN2, are involved in the processing and stability of miRNAs. However, the role of DIS3 on the regulation of miRNAs remains largely unknown. Here we found that DIS3 regulates the levels of the tumor suppressor let-7 miRNAs without affecting other miRNA families. DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing. DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis. Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation.
| Original language | English |
|---|---|
| Pages (from-to) | 5182-5193 |
| Number of pages | 12 |
| Journal | Nucleic Acids Research |
| Volume | 43 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Apr 12 2015 |
Fingerprint
ASJC Scopus subject areas
- Genetics
Cite this
The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA. / Segalla, Simona; Pivetti, Silvia; Todoerti, Katia; Chudzik, Malgorzata Agata; Giuliani, Erica Claudia; Lazzaro, Federico; Volta, Viviana; Lazarevic, Dejan; Musco, Giovanna; Muzi-Falconi, Marco; Neri, Antonino; Biffo, Stefano; Tonon, Giovanni.
In: Nucleic Acids Research, Vol. 43, No. 10, 12.04.2015, p. 5182-5193.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA
AU - Segalla, Simona
AU - Pivetti, Silvia
AU - Todoerti, Katia
AU - Chudzik, Malgorzata Agata
AU - Giuliani, Erica Claudia
AU - Lazzaro, Federico
AU - Volta, Viviana
AU - Lazarevic, Dejan
AU - Musco, Giovanna
AU - Muzi-Falconi, Marco
AU - Neri, Antonino
AU - Biffo, Stefano
AU - Tonon, Giovanni
PY - 2015/4/12
Y1 - 2015/4/12
N2 - Multiple myeloma, the second most frequent hematologic tumor after lymphomas, is an incurable cancer. Recent sequencing efforts have identified the ribonuclease DIS3 as one of the most frequently mutated genes in this disease. DIS3 represents the catalytic subunit of the exosome, a macromolecular complex central to the processing, maturation and surveillance of various RNAs. miRNAs are an evolutionarily conserved class of small noncoding RNAs, regulating gene expression at post-transcriptional level. Ribonucleases, including Drosha, Dicer and XRN2, are involved in the processing and stability of miRNAs. However, the role of DIS3 on the regulation of miRNAs remains largely unknown. Here we found that DIS3 regulates the levels of the tumor suppressor let-7 miRNAs without affecting other miRNA families. DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing. DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis. Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation.
AB - Multiple myeloma, the second most frequent hematologic tumor after lymphomas, is an incurable cancer. Recent sequencing efforts have identified the ribonuclease DIS3 as one of the most frequently mutated genes in this disease. DIS3 represents the catalytic subunit of the exosome, a macromolecular complex central to the processing, maturation and surveillance of various RNAs. miRNAs are an evolutionarily conserved class of small noncoding RNAs, regulating gene expression at post-transcriptional level. Ribonucleases, including Drosha, Dicer and XRN2, are involved in the processing and stability of miRNAs. However, the role of DIS3 on the regulation of miRNAs remains largely unknown. Here we found that DIS3 regulates the levels of the tumor suppressor let-7 miRNAs without affecting other miRNA families. DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing. DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis. Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation.
UR - http://www.scopus.com/inward/record.url?scp=84931287862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84931287862&partnerID=8YFLogxK
U2 - 10.1093/nar/gkv387
DO - 10.1093/nar/gkv387
M3 - Article
C2 - 25925570
AN - SCOPUS:84931287862
VL - 43
SP - 5182
EP - 5193
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 10
ER -