Loss of the Drosophila melanogaster DEAD box protein Ddx1 leads to reduced size and aberrant gametogenesis

Germain, Devon R.; Li, Lei; Hildebrandt, Matthew R.; Simmonds, Andrew; Hughes, Sarah C.; Godbout, Roseline

doi:10.1016/j.ydbio.2015.09.012

Cited by 17 publications

(11 citation statements)

References 69 publications

(87 reference statements)

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“…18 Because DDX1 deficiency in mice causes early embryonic lethality, it must play essential roles in normal cells. 19 DDX1 plays a critical role in testicular tumorigenesis in part by promoting transcription of Cyclin-D2 and stem cell-related genes on human chromosome 12p. 20 The expression level of DDX1 is elevated not only in germ cell tumors but also in retinoblastoma, neuroblastoma, glioblastoma and breast cancer.…”

Section: Ddx1mentioning

confidence: 99%

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DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene

et al. 2018

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DDX1, a member of the DEAD box RNA helicase family, plays a critical role in testicular tumors. However, it remains to be clarified whether DDX1 is involved in other types of malignant tumors such as colorectal cancer. We disrupted the DDX1 gene in a human colorectal cancer cell line LoVo using the CRISPR/Cas9‐mediated gene‐targeting system. DDX1‐KO LoVo cells exhibited a much slower growth rate, produced fewer colonies in soft agar medium, and generated smaller solid tumors in nude mice than parental LoVo cells. Such phenotypes of the DDX1‐KO cells were mostly reversed by exogenous expression of DDX1. These results indicate that DDX1 is required for tumorigenicity of colorectal cancer cells. In the DDX1‐KO cells, the cancer stem cell marker genes LGR5, CD133, ALDH1 and SOX2 were markedly suppressed. Among them, expression of LGR5, which is essential for tumorigenicity of colorectal cancer cells, was restored in the DDX1‐transfected DDX1‐KO cells. Consistently, the DDX1‐KO cells lost sphere‐forming capacity in a DDX1‐dependent fashion. Reporter and chromatin immunoprecipitation assays revealed that DDX1 directly bound to the −1837 to −1662 region of the enhancer/promoter region of the human LGR5 gene and enhanced its transcription in LoVo cells. Repression of LGR5 by DDX1 knockdown was observed in 2 other human colorectal cancer cell lines, Colo320 and SW837. These results suggest that LGR5 is a critical effector of DDX1 in colorectal cancer cells. The DDX1‐LGR5 axis could be a new drug target for this type of malignant cancer.

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Section: Ddx1mentioning

confidence: 99%

“…DDX1 is involved in a variety of biological processes, including tRNA synthesis, mRNA and microRNA processing, ribosome biogenesis, DNA repair, and nuclear factor‐kappaB‐mediated gene induction . Because DDX1 deficiency in mice causes early embryonic lethality, it must play essential roles in normal cells …”

Section: Introductionmentioning

confidence: 99%

DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene

et al. 2018

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“…The DEAD box 1 gene (DDX1) is a widely expressed gene that is misexpressed in a number of cancers, including retinoblastoma, neuroblastoma, and breast cancer (1,2). Knockout of DDX1 leads to early embryonic lethality in mice and severely reduced fertility in flies (3,4). DDX1 is involved in the transport of RNAs from the nucleus to the cytoplasm and regulates cytoplasmic localization of the splicing-regulatory protein KSRP (5).…”

mentioning

confidence: 99%

DEAD Box 1 Facilitates Removal of RNA and Homologous Recombination at DNA Double-Strand Breaks

Germain

Poon

et al. 2016

Molecular and Cellular Biology

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Although RNA and RNA-binding proteins have been linked to double-strand breaks (DSBs), little is known regarding their roles in the cellular response to DSBs and, if any, in the repair process. Here, we provide direct evidence for the presence of RNA-DNA hybrids at DSBs and suggest that binding of RNA to DNA at DSBs may impact repair efficiency. Our data indicate that the RNAunwinding protein DEAD box 1 (DDX1) is required for efficient DSB repair and cell survival after ionizing radiation (IR), with depletion of DDX1 resulting in reduced DSB repair by homologous recombination (HR). While DDX1 is not essential for end resection, a key step in homology-directed DSB repair, DDX1 is required for maintenance of the single-stranded DNA once generated by end resection. We show that transcription deregulation has a significant effect on DSB repair by HR in DDX1-depleted cells and that RNA-DNA duplexes are elevated at DSBs in DDX1-depleted cells. Based on our combined data, we propose a role for DDX1 in resolving RNA-DNA structures that accumulate at DSBs located at sites of active transcription. Our findings point to a previously uncharacterized requirement for clearing RNA at DSBs for efficient repair by HR. DEAD box proteins are a family of putative RNA helicases that function by altering RNA secondary structure. This protein family has been implicated in all aspects of RNA metabolism. The DEAD box 1 gene (DDX1) is a widely expressed gene that is misexpressed in a number of cancers, including retinoblastoma, neuroblastoma, and breast cancer (1, 2). Knockout of DDX1 leads to early embryonic lethality in mice and severely reduced fertility in flies (3, 4). DDX1 is involved in the transport of RNAs from the nucleus to the cytoplasm and regulates cytoplasmic localization of the splicing-regulatory protein KSRP (5). In neurons, DDX1 resides in RNA-transporting granules, cytoplasmic organelles that regulate the localization and expression of target mRNAs (6, 7). DDX1 has also been identified as a core subunit of the human tRNA ligase complex which is essential for tRNA splicing (8).In addition to its roles in RNA metabolism, DDX1 has been implicated in the cellular response to DNA double-strand breaks (DSBs). Upon treatment of cells with ionizing radiation (IR), DDX1 rapidly accumulates at a subset of DNA DSBs (ϳ30%), where it forms IR-induced foci that colocalize with ␥-H2AX, a marker for DSBs (9). DDX1 coimmunoprecipitates with the MRN (MRE11-RAD50-NBS1) complex, the early sensor of DNA DSBs, and ATM (ataxia telangiectasia mutated) protein, the key transducer of the signaling cascade in response to DSBs (10, 11). DSBs induce DDX1 phosphorylation in an ATM-dependent manner. Notably, IR-induced DDX1 foci are lost when cells are treated with RNase H, an enzyme that specifically digests RNA from RNA-DNA hybrids (9). These results suggest that RNA-DNA double-stranded structures are required for the presence and/or retention of DDX1 at DSBs. In line with this observation, biochemical analysis has shown that DDX1 can unwind both...

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“…DDX1 null flies were infertile, significantly smaller, and developmentally delayed, with both oogenesis and spermatogenesis affected. Significantly smaller ovaries containing few to no mature eggs were observed in DDX1 null flies ( Germain et al., 2015 ). DDX1 was highly expressed in the developing oocytes and the surrounding granulosa cells of the ovaries.…”

Section: Discussionmentioning

confidence: 99%

The Potential Role of MicroRNA‐124‐3p in Growth, Development, and Reproduction of Schistosoma japonicum

Zhou

Hong

Shang

et al. 2022

Front. Cell. Infect. Microbiol.

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The microRNA‐124‐3p plays an important role in regulating development and neurogenesis. Previous microRNA sequencing analyses of Schistosoma japonicum revealed sja-miR-124-3p differential expression patterns in schistosomes from different hosts and at different developmental stages. This study explores the regulatory role of sja-miR-124-3p in S. japonicum development and reproduction. Quantitative reverse-transcription PCR (qRT-PCR) showed that the expression level of sja-miR-124-3p in S. japonicum from resistant hosts, such as Microtus fortis, and unsuitable hosts, such as rats and water buffalo, was significantly higher than that in mice and yellow cattle at the same developmental stage. Overexpressing sja-miR-124-3p in infected mice led to a hepatic egg reduction rate of 36.97%, smaller egg granulomas in the livers, increased liver weight, subsided hepatocyte necrosis, and diminished inflammatory cell infiltration. The width of female worms increased but decreased in males. The vitelline cells were irregular, swollen, or fused. The teguments and ventral sucker of males and females were swollen and broken, but the morphological changes were particularly notable in males. qRT-PCR and dual-luciferase reporter assay system were used to confirm the in-silico-predicted target genes, S. japonicum DEAD-box ATP-dependent RNA helicase 1 (sjDDX1) and DNA polymerase II subunit 2 (sjPOLE2). Our results showed that RNA interference (RNAi)-mediated sjDDX1 silencing in mice provided a 24.55% worm reduction rate and an 18.36% egg reduction rate, but the difference was not significant (p > 0.05). Thus, our findings suggest that sja-miR-124-3p has an important role in growth, development, and reproduction in S. japonicum. All these results will greatly contribute toward providing important clues for searching vaccine candidates and new drug targets against schistosomiasis.

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Loss of the Drosophila melanogaster DEAD box protein Ddx1 leads to reduced size and aberrant gametogenesis

Cited by 17 publications

References 69 publications

DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene

DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene

DEAD Box 1 Facilitates Removal of RNA and Homologous Recombination at DNA Double-Strand Breaks

The Potential Role of MicroRNA‐124‐3p in Growth, Development, and Reproduction of Schistosoma japonicum

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