DEAD-box RNA helicase Dbp2 binds to G-quadruplex nucleic acids and regulates different conformation of G-quadruplex DNA

Song, Qinxia; Lai, Chang-Wei; Liu, Na-Nv; Hou, Xi-Miao; Xi, Xu-Guang

doi:10.1016/j.bbrc.2022.10.004

“…For example, in regard to DDX5 acting as a transcription co-activator to upregulate the expression of different genes in the case of DDX5 in resolving G-quadruplexes (G4) structure for transcription, Wu et al reported that DDX5 is extremely proficient at unfolding a DNA G4 structure in the Myc proximal promoter region (MycG4 that functions as a transcriptional silencer) to turn on the Myc oncogene expression in breast and prostate cancer [ 55 ]. Song et al reported that Dbp2 (the yeast DDX5) binds MycG4 with a high affinity to resolve the MycG4 structure and to have stronger MycG4 folding-promoting activity than DDX5 [ 56 ]. Diffendall et al reported that in parasites, Plasmodium falciparum (Pf), Pf-DDX5 interacts with the non-coding RNA (ncRNA) RUF6 in the RUF6 protein complex that interacts with RNA Pol II to promote the expression of the human host-interacting var gene of Pf for progression, which is likely through resolving the G4 structures in the var gene [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Li,

Ling,

Chakraborty

et al. 2023

J Exp Clin Cancer Res

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There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5’s role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

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“…The nucleic acid substrate-specific biochemical properties of Dbp5 ATPase regulation defined here may have wide-ranging implications for Dbp5 functions in pre-ribosomal RNA export, translation, or R-loop metabolism. Furthermore, several DEAD-box proteins such as Dbp2 have been reported to bind diverse nucleic acid substrates (ncRNA and mRNA), including G-Quadraplexes, and have roles in R-loop biology ( Ma et al, 2016 ; Xing et al, 2017 ; Tedeschi et al, 2018 ; Gao et al, 2019 ; Lai et al, 2019 ; Lai and Tran, 2021 ; Yan et al, 2021 ; Song et al, 2022 ). Given the high degree of conservation in the structure, function, and regulation of Dbp5 with other DEAD-box proteins ( Ozgur et al, 2015 ; Sloan and Bohnsack, 2018 ), the observations reported here raise the possibility that other DEAD-box proteins may also demonstrate substrate-specific regulation.…”

Section: Discussionmentioning

confidence: 99%

Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and promote Dbp5-mediated tRNA export in vivo in Saccharomyces cerevisiae

Arul Nambi Rajan,

Asada,

Montpetit

2024

eLife

0

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Cells must maintain a pool of processed and charged transfer RNAs (tRNA) to sustain translation capacity and efficiency. Numerous parallel pathways support the processing and directional movement of tRNA in and out of the nucleus to meet this cellular demand. Recently, several proteins known to control messenger RNA (mRNA) transport were implicated in tRNA export. The DEAD-box Protein 5, Dbp5, is one such example. In this study, genetic and molecular evidence demonstrates that Dbp5 functions parallel to the canonical tRNA export factor Los1. In vivo co-immunoprecipitation data further shows Dbp5 is recruited to tRNA independent of Los1, Msn5 (another tRNA export factor), or Mex67 (mRNA export adaptor), which contrasts with Dbp5 recruitment to mRNA that is abolished upon loss of Mex67 function. However, as with mRNA export, overexpression of Dbp5 dominant-negative mutants indicates a functional ATPase cycle and that binding of Dbp5 to Gle1 is required by Dbp5 to direct tRNA export. Biochemical characterization of the Dbp5 catalytic cycle demonstrates the direct interaction of Dbp5 with tRNA (or double stranded RNA) does not activate Dbp5 ATPase activity, rather tRNA acts synergistically with Gle1 to fully activate Dbp5. These data suggest a model where Dbp5 directly binds tRNA to mediate export, which is spatially regulated via Dbp5 ATPase activation at nuclear pore complexes by Gle1.

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“…The nucleic acid substrate-specific biochemical properties of Dbp5 ATPase regulation defined here may have wide-ranging implications for Dbp5 functions in pre-ribosomal RNA export, translation, or R-loop metabolism. Furthermore, several DEAD-box proteins such as Dbp2 have been reported to bind diverse nucleic acid substrates (ncRNA and mRNA), including G-Quadraplexes, and have roles in R-loop biology (Ma, Paudel et al 2016, Xing, Wang et al 2017, Tedeschi, Cloutier et al 2018, Gao, Byrd et al 2019, Lai, Choudhary et al 2019, Lai and Tran 2021, Yan, Obi et al 2021, Song, Lai et al 2022). Given the high degree of conservation in the structure, function, and regulation of Dbp5 with other DEAD-box proteins (Ozgur, Buchwald et al 2015, Sloan and Bohnsack 2018), the observations reported here raise the possibility that other DEAD-box proteins may also demonstrate substrate-specific regulation.…”

Section: Discussionmentioning

confidence: 99%

Gle1 is required for tRNA to stimulate Dbp5 ATPase activityin vitroand to promote Dbp5 mediated tRNA exportin vivo

Rajan

¹

,

Asada

²

,

Montpetit

³

2023

Preprint

0

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Cells must maintain a pool of processed and charged transfer RNAs (tRNA) to sustain translation capacity and efficiency. Numerous parallel pathways support the processing and directional movement of tRNA in and out of the nucleus to meet this cellular demand. Recently, several proteins known to control messenger RNA (mRNA) transport were implicated in tRNA export. The DEAD-box Protein 5, Dbp5, is one such example. In this study, genetic and molecular evidence demonstrates that Dbp5 functions parallel to the canonical tRNA export factor Los1. In vivo co-immunoprecipitation data further shows Dbp5 is recruited to tRNA independent of Los1, Msn5 (another tRNA export factor), or Mex67 (mRNA export adaptor), which contrasts with Dbp5 recruitment to mRNA that is abolished upon loss of Mex67 function. However, as with mRNA export, overexpression of Dbp5 dominant-negative mutants indicates a functional ATPase cycle and that binding of Dbp5 to Gle1 is required by Dbp5 to direct tRNA export. Biochemical characterization of the Dbp5 catalytic cycle demonstrates the direct interaction of Dbp5 with tRNA (or double stranded RNA) does not activate Dbp5 ATPase activity, rather tRNA acts synergistically with Gle1 to fully activate Dbp5. These data suggest a model where Dbp5 directly binds tRNA to mediate export, which is spatially regulated via Dbp5 ATPase activation at nuclear pore complexes by Gle1.

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DEAD-box RNA helicase Dbp2 binds to G-quadruplex nucleic acids and regulates different conformation of G-quadruplex DNA

Cited by 11 publications

References 44 publications

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and promote Dbp5-mediated tRNA export in vivo in Saccharomyces cerevisiae

Gle1 is required for tRNA to stimulate Dbp5 ATPase activityin vitroand to promote Dbp5 mediated tRNA exportin vivo

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