DICER1: mutations, microRNAs and mechanisms

Abstract

Dicer is central to microRNA-mediated silencing and several other RNA interference phenomena that are profoundly embedded in cancer gene networks. Most recently, both germline and somatic mutations in DICER1 have been identified in diverse types of cancer. Although some of the mutations clearly reduce the dosage of this key enzyme, others dictate surprisingly specific changes in select classes of small RNAs. This Review reflects on the molecular properties of the Dicer enzymes in small RNA silencing pathways, and rationalizes the newly discovered mutations on the basis of the activities and functions of its determinants.

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

“…In general, DICER1 levels are decreased in different types of human tumors and germline mutations in DICER1 are associated with a rare type of childhood cancer called pleuropulmonary blastoma (PPB) (Bahubeshi et al ., 2011; Foulkes et al ., 2014). Point mutations in DICER1 have also been described leading to tumor predisposition and referred to as DICER1 syndrome (Bahubeshi et al ., 2011; Foulkes et al ., 2014).…”

“…In general, DICER1 levels are decreased in different types of human tumors and germline mutations in DICER1 are associated with a rare type of childhood cancer called pleuropulmonary blastoma (PPB) (Bahubeshi et al ., 2011; Foulkes et al ., 2014). Point mutations in DICER1 have also been described leading to tumor predisposition and referred to as DICER1 syndrome (Bahubeshi et al ., 2011; Foulkes et al ., 2014). However, the role of DICER1 in cancer is complicated as mouse cancer models suggest that loss of one copy of the Dicer1 gene increases tumorigenesis, whereas loss of both copies inhibits it, leading to the idea that DICER1 functions as a haploinsufficient tumor suppressor (Bahubeshi  et al ., 2011; Foulkes et al ., 2014).…”

“…Point mutations in DICER1 have also been described leading to tumor predisposition and referred to as DICER1 syndrome (Bahubeshi et al ., 2011; Foulkes et al ., 2014). However, the role of DICER1 in cancer is complicated as mouse cancer models suggest that loss of one copy of the Dicer1 gene increases tumorigenesis, whereas loss of both copies inhibits it, leading to the idea that DICER1 functions as a haploinsufficient tumor suppressor (Bahubeshi  et al ., 2011; Foulkes et al ., 2014). These pieces of evidence may reflect the importance of DICER1 on cell survival and/or indicate that a subset of miRNAs is important for cancer progression.…”

“…In general with few exceptions, cancer cells have decreased global miRNA expression (Lu et al ., 2005; Kumar et al ., 2007), leading to the hypothesis that upregulation of DICER1 may lead to increased miRNA expression, which would then contribute to lowering tumorigenic activity. Consistent with this idea, DICER1 expression is decreased in several types of human cancers (Bahubeshi et al ., 2011; Foulkes et al ., 2014). …”

Seltene Tumordispositionssyndrome mit Manifestation im Kindesalter

“…Zudem ist DICER1 bei der Bildung des "RNA-induced silencing complex" (RISC) und der Vermittlung von Protein-Protein-Interaktion von Bedeutung. miRNAs spielen eine entscheidende Rolle bei der posttranskriptionellen Regulation der Genexpression ihrer Zielgene, indem sie die Proteinexpression durch Translationsrepression sowie Deadenylierung und Abbau der mRNA hemmen [62,63].…”