DICER1 syndrome

View Details

Status

Done

DICER1 gene

On chromosome 14q32.13

Can be regarded

A tumor suppressor gene due to loss-of-function mutations OR

It is thought to function as a haploinsufficient tumor suppressor gene with the loss of one allele leading to tumor progression
Loss of both alleles having an inhibitory effect for tumor development implying that one intact allele is needed for cell survival

An oncogene due to gain-of-function mutations;

Function

Control of protein translation

DICER 1 gene product = dicer protein

A ribonuclease (RNase) III endoribonuclease which is essential for the production of microRNAs (miRNA) which are formed by the cleavage of pre-miRNA or double-stranded RNA
RNase III contains two domains, IIIa and IIIb which cleave 3p miRNA and 5p miRNA from the 3′ and 5′ pre-miRNA, respectively

notion image

miRNA processing in ETMRs

Step 1: C19MC miRNAs are transcribed by RNA polymerase (RNA POL) into long non-coding RNA precursors (pri-miRNAs).

Step 2: The pri-miRNAs are processed in the nucleus by the microprocessor complex, which includes DGCR8 and DROSHA, generating pre-miRNAs.

Step 3: These pre-miRNAs are exported out of the nucleus by exportin-5 (XPO5) in complex with RAN.

Step 4: In the cytoplasm, DICER (along with TRBP) further cleaves the pre-miRNA into two mature miRNA strands: the 5p and 3p forms.

Step 5: One strand (either 5p or 3p, depending on the miRNA) is loaded into the Argonaute protein (AGO) to form the RNA-induced silencing complex (RISC); the other strand is usually degraded.

Step 6: The RISC complex uses the miRNA as a guide to bind target mRNA via the seed sequence.

Step 7: The outcome for the target mRNA can be repression of translation (red), degradation of mRNA (red), or formation of a scaffold (green), depending on the context. The coloring reflects whether translation decreases (red) or increases (green).

RNA C19MC POL R NA polyrnerase transcribes C 19MC miRNAs Long non-coding RNA containing pri-miRNAs DGCR8 DROSHA Drosha/DGCR8 process pri-rniRNAs into pre-miRNAs Nucleus XP05 Cytoplasm 4 RAN P05 exports pre-rniRNA out of the nucleus C19MC target genes Repression Of translation Degradation Of mRNA Formation Of a scaffold TTTTTT- DICER TRBP TTTTTTTT— 3p DICER IfTRBP cleave the pre-mRNA forming two mature miRNAs 5p dominant miRNAs 3p inant miRNAs DICER : TRBP DICER TRBP Wildtype DICERI 3p TTTTTT— ITTlTT•rr 3p AGO AGO DICE-RI RNASE-III mutations DICER TRBP 3p TTTTT•r DICER TRBP 3p AGO miRNAs are processed normally Abundance of 5p mature miRNAs is reduced U.U.UU.U.U.UU.UII.U @ RISC binds mRNA using seed sequence AGO One strand gets @ loaded In AGO and forms the RISC Degradation of one strand Loss of function Dicerl DICER TRBP DICER TRBP All miRNAs are depleted miRNA processing in ETMRs. a Overview of miRNA processing and maturation using the ClgMC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC. b Overview of different scenarios that mutations in DICERI have on the abundance of 3p and 5p forms of mature miRNAs — (a) Overview of miRNA processing and maturation using the C19MC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC.

Wildtype DICER1 (left):

Both 5p and 3p mature miRNAs are correctly processed. The dominant strand is loaded onto AGO and the non-dominant strand is degraded. miRNAs function normally.

DICER1 RNASE-III mutations (middle):

These mutations mainly affect the 5p processing. As a result, the amount of 5p mature miRNAs is reduced while 3p processing may be less affected.
Lead to Embryonal tumour with multi-layered rosettes, C19MC-altered

Loss-of-function DICER1 (right):

Both 5p and 3p mature miRNAs are severely depleted, and virtually no mature miRNAs are produced, resulting in wholesale loss of miRNA-mediated regulation.
Leads to Embryonal tumour with multi-layered rosettes, DICER1-altered

RNA C19MC POL R NA polyrnerase transcribes C 19MC miRNAs Long non-coding RNA containing pri-miRNAs DGCR8 DROSHA Drosha/DGCR8 process pri-rniRNAs into pre-miRNAs Nucleus XP05 Cytoplasm 4 RAN P05 exports pre-rniRNA out of the nucleus C19MC target genes Repression Of translation Degradation Of mRNA Formation Of a scaffold TTTTTT- DICER TRBP TTTTTTTT— 3p DICER IfTRBP cleave the pre-mRNA forming two mature miRNAs 5p dominant miRNAs 3p inant miRNAs DICER : TRBP DICER TRBP Wildtype DICERI 3p TTTTTT— ITTlTT•rr 3p AGO AGO DICE-RI RNASE-III mutations DICER TRBP 3p TTTTT•r DICER TRBP 3p AGO miRNAs are processed normally Abundance of 5p mature miRNAs is reduced U.U.UU.U.U.UU.UII.U @ RISC binds mRNA using seed sequence AGO One strand gets @ loaded In AGO and forms the RISC Degradation of one strand Loss of function Dicerl DICER TRBP DICER TRBP All miRNAs are depleted miRNA processing in ETMRs. a Overview of miRNA processing and maturation using the ClgMC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC. b Overview of different scenarios that mutations in DICERI have on the abundance of 3p and 5p forms of mature miRNAs — (b) Overview of different scenarios that mutations in DICER1 have on the abundance of 3p and 5p forms of mature miRNAs.

DICER1 Status	5p miRNA	3p miRNA	Overall Processing
Wildtype	Normal	Normal	Normal miRNA maturation
RNASE-III Mutations	Reduced	Normal	5p dominant miRNAs are reduced
Loss-of-function DICER1	Depleted	Depleted	All miRNAs depleted

Associated with the following CNS tumours

Pituitary blastoma

Pineoblastoma

Embryonal tumor with multilayered rosettes

Made with Bullet