A druggable target for rescuing microRNA defects

Asada, Ken; Canestrari, Emanuele; Paroo, Zain

doi:10.1016/j.bmcl.2016.09.019

Cited by 6 publications

(3 citation statements)

References 43 publications

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“…In these tumors, unprocessed pre-miRNAs are degraded by the endonuclease complex TSN-TSNAX. Pharmacological or shRNA-mediated inhibition of this complex facilitates the restoration of miRNA levels by DICER1 in vitro, making it a potential therapeutic target [153,154]. This strategy, however, has not yet been explored in tumors carrying DICER1 hotspot variants.…”

Section: Dicer1mentioning

confidence: 99%

Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors

Torres-Morán,

Franco-Álvarez,

Rebollar-Vega

et al. 2023

Cancers

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The most common genetic drivers of pituitary neuroendocrine tumors (PitNETs) lie within mutational hotspots, which are genomic regions where variants tend to cluster. Some of these hotspot defects are unique to PitNETs, while others are associated with additional neoplasms. Hotspot variants in GNAS and USP8 are the most common genetic causes of acromegaly and Cushing’s disease, respectively. Although it has been proposed that these genetic defects could define specific clinical phenotypes, results are highly variable among studies. In contrast, DICER1 hotspot variants are associated with a familial syndrome of cancer predisposition, and only exceptionally occur as somatic changes. A small number of non-USP8-driven corticotropinomas are due to somatic hotspot variants in USP48 or BRAF; the latter is a well-known mutational hotspot in cancer. Finally, somatic variants affecting a hotspot in SF3B1 have been associated with multiple cancers and, more recently, with prolactinomas. Since the associations of BRAF, USP48, and SF3B1 hotspot variants with PitNETs are very recent, their effects on clinical phenotypes are still unknown. Further research is required to fully define the role of these genetic defects as disease biomarkers and therapeutic targets.

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Section: Dicer1mentioning

confidence: 99%

Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors

Torres-Morán,

Franco-Álvarez,

Rebollar-Vega

et al. 2023

Cancers

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“…Here we provide the first mechanistic insight into how conserved Translin function might be linked to genomic changes such as translocations, drivers of evolution and disease. Importantly, given that Translin has been targeted as a potential therapeutic target in oncology and other disorders [13][14][15], these findings also provide insight to inform rational therapeutic design to ensure that only disease associated function(s) are targeted, and also exposes new synthetic lethality therapeutic options should it be found that Translin provides an auxiliary function in Dicer deficiency in human cells. (A) RT-qPCR analysis of expression of rnh1 + in distinct strains.…”

Section: Plos Geneticsmentioning

confidence: 99%

“…Inhibition of Tn-Tx in Dicer-limited cancer cells permits the residual Dicer to re-establish appropriate maturation of pre-miRNAs [ 14 ]. Indeed, small molecule inhibitors of Tn-Tx RNase activity have been developed that enable pre-miRNA maturation by Dicer, demonstrating the therapeutic potential of targeting Tn-Tx in Dicer-limited cancers [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Translin facilitates RNA polymerase II dissociation and suppresses genome instability during RNase H2- and Dicer-deficiency

et al. 2022

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The conserved nucleic acid binding protein Translin contributes to numerous facets of mammalian biology and genetic diseases. It was first identified as a binder of cancer-associated chromosomal translocation breakpoint junctions leading to the suggestion that it was involved in genetic recombination. With a paralogous partner protein, Trax, Translin has subsequently been found to form a hetero-octomeric RNase complex that drives some of its functions, including passenger strand removal in RNA interference (RNAi). The Translin-Trax complex also degrades the precursors to tumour suppressing microRNAs in cancers deficient for the RNase III Dicer. This oncogenic activity has resulted in the Translin-Trax complex being explored as a therapeutic target. Additionally, Translin and Trax have been implicated a wider range of biological functions ranging from sleep regulation to telomere transcript control. Here we reveal a Trax- and RNAi-independent function for Translin in dissociating RNA polymerase II from its genomic template, with loss of Translin function resulting in increased transcription-associated recombination and elevated genome instability. This provides genetic insight into the longstanding question of how Translin might influence chromosomal rearrangements in human genetic diseases and provides important functional understanding of an oncological therapeutic target.

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