Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum

Swahari, Vijay; Nakamura, Ayumi; Baran-Gale, Jeanette; García, Idoia; Crowther, Andrew; Sons, Robert; Gershon, Timothy R.; Hammond, Scott M.; Sethupathy, Praveen; Deshmukh, Mohanish

doi:10.1016/j.celrep.2015.12.037

Cited by 44 publications

(37 citation statements)

References 46 publications

(54 reference statements)

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“…Moreover, Dicer deficiency leads to accumulation of DNA damage in these cells, causing apoptosis. Similar observations were made in rapidly proliferating, Dicer-deficient medulloblastoma cells in which the cells are more sensitive to DNA damaging agents and exhibit increased cell death when compared to wild-type tumours [53]. This study indicates that Dicer is involved in DNA repair.…”

Section: Dicer In Maintenance Of Genome Integritysupporting

confidence: 81%

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

Pong

Gullerová

2018

FEBS Letters

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MicroRNAs (miRNAs) are small regulatory noncoding RNAs that are generated in the canonical RNA interference (RNAi) pathway. Drosha, DiGeorge syndrome critical region 8 (DGCR8) and Dicer are key players in miRNA biogenesis. Argonaute (Ago) proteins bind to miRNAs and are guided by them to find messenger RNA targets and carry out post-transcriptional silencing of protein-coding genes. Recently, emerging evidence suggests that RNAi factors have a range of noncanonical functions that are beyond miRNA biogenesis. These functions pertain to various biological processes, such as development, transcriptional regulation, RNA processing and maintenance of genome integrity. Here, we review recent literature reporting miRNA-independent, noncanonical functions of Drosha, DGCR8, Dicer and Ago proteins and discuss the importance of these functions.

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Section: Dicer In Maintenance Of Genome Integritysupporting

confidence: 81%

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

Pong

Gullerová

2018

FEBS Letters

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“…DNA damage and apoptosis caused by depletion of Dicer or Dgcr8 have been reported in cerebellum neuronal precursors, which makes the miRNA biogenesis pathway a potential target to inhibit cerebellar tumors [38]. In this study, we demonstrated that disruption of Dgcr8 in cortexderived NSCs also exhibit increased DNA damage (Fig.…”

Section: Dgcr8supporting

confidence: 49%

“…5E-G). These data demonstrated that, just like the cerebellum neural progenitors [38], loss of -/-NSCs rescued by a DGCR8 cDNA into neurons, astrocytes, and oligodendrocytes. Immunostaining of (C) neuronal markers Tuj1 (green) and MAP2 (red), (C¢) astrocyte-specific marker GFAP (red) and DAPI (blue), and (C †) oligodendrocyte-specific marker O1 (green (n = 121) NSCs.…”

Section: Loss Of Canonical Mirnas Causes Dna Damage In Nscsmentioning

confidence: 78%

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Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

Liu

Zhang

Khodadadi‐Jamayran

et al. 2017

Stem Cells and Development

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Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8 -/-NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/-NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/-NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8 +/-NSCs, Dgcr8 -/-NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8 -/-NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8 -/-NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8 -/-NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs.

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“…Deletion of Dicer or Dgcr8 in the developing mouse brain leads to increased DNA damage (Swahari et al, 2016). Furthermore, small non-coding RNAs, termed DNA damage-response RNAs (DDRNAs) or double-strand break (DSB)-induced RNAs (diRNAs), generated at sites of DNA damage are involved in DNA damage response after DSB generation (Francia et al, 2016; Francia et al, 2012) (Wei et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

DGCR8 Mediates Repair of UV-Induced DNA Damage Independently of RNA Processing

et al. 2017

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SUMMARY Ultraviolet (UV) radiation is a carcinogen that generates DNA lesions. Here we demonstrate an unexpected role for DGCR8, an RNA binding protein that canonically functions with Drosha to mediate microRNA processing, in the repair of UV-induced DNA lesions. Treatment with UV induced phosphorylation on Serine 153 (S153) of DGCR8 in human and murine cells. S153 phosphorylation was critical for cellular resistance to UV, the removal of UV-induced DNA lesions, and the recovery of RNA synthesis after UV exposure, but not for microRNA expression. The RNA-binding and Drosha-binding activities of DGCR8 were not critical for UV resistance. DGCR8 depletion was epistatic to defects in XPA, CSA and CSB for UV sensitivity. DGCR8 physically interacted with CSB and RNA polymerase II. JNKs were involved in the UV-induced S153 phosphorylation. These findings suggest that UV-induced S153 phosphorylation mediates transcription-coupled nucleotide excision repair of UV-induced DNA lesions in a manner independent of microRNA processing.

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Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum

Cited by 44 publications

References 46 publications

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

DGCR8 Mediates Repair of UV-Induced DNA Damage Independently of RNA Processing

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