ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA

Wollen, Kristian Lied; Hagen, Lars; Vågbø, Cathrine Broberg; Rabe, Renana; Iveland, Tobias S.; Arne, Per; Sharma, Animesh; Sporsheim, Bjørnar; Erlandsen, Hilde O.; Palibrk, Vuk; Bjørås, Magnar; Fonseca, D. M.; Mosammaparast, Nima; Slupphaug, Geir

doi:10.1186/s12967-021-02948-6

Cited by 16 publications

(17 citation statements)

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“…GEMIN5 regulates mRNA splicing and tumour cell motility ( 36 ). In addition, GEMIN5 has a key role in reprogramming cellular translation ( 37 ). We selected chemotherapy drugs that are currently used for the treatment of GC evaluated the effect of patients in the two groups to these drugs.…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a m7G-Related Gene-Based Prognostic Model for Gastric Cancer

Wang

Chen

et al. 2022

Front. Oncol.

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BackgroundGastric cancer (GC) is one of the most common malignant tumors of the digestive system. Chinese cases of GC account for about 40% of the global rate, with approximately 1.66 million people succumbing to the disease each year. Despite the progress made in the treatment of GC, most patients are diagnosed at an advanced stage due to the lack of obvious clinical symptoms in the early stages of GC, and their prognosis is still very poor. The m7G modification is one of the most common forms of base modification in post-transcriptional regulation, and it is widely distributed in the 5′ cap region of tRNA, rRNA, and eukaryotic mRNA.MethodsRNA sequencing data of GC were downloaded from The Cancer Genome Atlas. The differentially expressed m7G-related genes in normal and tumour tissues were determined, and the expression and prognostic value of m7G-related genes were systematically analysed. We then built models using the selected m7G-related genes with the help of machine learning methods.The model was then validated for prognostic value by combining the receiver operating characteristic curve (ROC) and forest plots. The model was then validated on an external dataset. Finally, quantitative real-time PCR (qPCR) was performed to detect gene expression levels in clinical gastric cancer and paraneoplastic tissue.ResultsThe model is able to determine the prognosis of GC samples quantitatively and accurately. The ROC analysis of model has an AUC of 0.761 and 0.714 for the 3-year overall survival (OS) in the training and validation sets, respectively. We determined a correlation between risk scores and immune cell infiltration and concluded that immune cell infiltration affects the prognosis of GC patients. NUDT10, METTL1, NUDT4, GEMIN5, EIF4E1B, and DCPS were identified as prognostic hub genes and potential therapeutic agents were identified based on these genes.ConclusionThe m7G-related gene-based prognostic model showed good prognostic discrimination. Understanding how m7G modification affect the infiltration of the tumor microenvironment (TME) cells will enable us to better understand the TME’s anti-tumor immune response, and hopefully guide more effective immunotherapy methods.

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Section: Discussionmentioning

confidence: 99%

Construction and Validation of a m7G-Related Gene-Based Prognostic Model for Gastric Cancer

Wang

Chen

et al. 2022

Front. Oncol.

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“…Both of the latter principles have been shown to play a role during ASCC-related cellular processes. 9,10,14,15,19,38,39…”

Section: Discussionmentioning

confidence: 99%

“…18 Furthermore, ASCC3 is required for e cient, ALKBH3dependent removal of m 1 A and m 3 C modi cations from mRNAs, and for alkylation-induced P-body formation. 19 ASCC3 contributes to all of the above ASCC-related functions. It is a large nucleic acid-dependent NTPase that can act as a 3'-to-5' translocase/helicase.…”

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confidence: 99%

Extended DNA threading through a dual-engine motor module in the activating signal co-integrator complex

Jia

Hilal

Bohnsack

et al. 2022

Preprint

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Activating signal co-integrator complex (ASCC) supports diverse genome maintenance and gene expression processes. Its ASCC3 subunit is an unconventional nucleic acid helicase, harboring tandem Ski2-like NTPase/helicase cassettes crucial for ASCC functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. Here, we present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-ASC1/TRIP4 sub-module of ASCC. Unlike the related spliceosomal SNRNP200 RNA helicase, ASCC3 can thread substrates through both helicase cassettes. ASC1 docks on ASCC3 via a zinc nger domain and stimulates the helicase by positioning a C-terminal ASC1-homology domain next to the C-terminal helicase cassette of ASCC3, likely assisting the DNA exit. ASC1 binds ASCC3 mutually exclusively with the DNA/RNA dealkylase, ALKBH3, directing ASCC for speci c processes. Our ndings de ne ASCC3-ASC1/TRIP4 as a tunable motor module of ASCC that encompasses two cooperating ATPase/helicase units functionally expanded by ASC1/TRIP4. modi cation at position A4220 of 28S rRNA. 18 Furthermore, ASCC3 is required for e cient, ALKBH3dependent removal of m 1 A and m 3 C modi cations from mRNAs, and for alkylation-induced P-body formation. 19 ASCC3 contributes to all of the above ASCC-related functions. It is a large nucleic acid-dependent NTPase that can act as a 3'-to-5' translocase/helicase. 13,20 NTPase-fueled remodeling of nucleic acids or nucleic acid-protein complexes by ASCC3, therefore, likely constitute central activities for all of ASCC's diverse cellular roles. For example, during DNA alkylation damage repair, ASCC3 generates single-stranded DNA for dealkylation by ALKBH3. 13,14 Furthermore, mutations in conserved NTPase/helicase motifs of ASCC3 interfere with ASCC-mediated splitting of stalled ribosomes during ribosome or translation quality control [9][10][11][12] , and ASCC3 has been suggested to disassemble ribosomes collided on alkylated mRNAs for dealkylation by ALKBH3 19 .ASCC3 is an unconventional nucleic acid-dependent NTPase that is closely related to the spliceosomal RNA helicase, U5 small nuclear ribonucleoprotein 200 kDa (SNRNP200/BRR2). ASCC3 and SNRNP200 contain a tandem array of Ski2-like helicase cassettes (N-terminal cassette, NC; C-terminal cassette, CC), preceded by ~ 400-residue N-terminal regions that can auto-inhibit the helicase activities. [20][21][22] In SNRNP200, only the NC is an active NTPase and helicase, while the CC acts as an intra-molecular helicase co-factor. 21,23 In contrast, both helicase cassettes in ASCC3 may be enzymatically active. 12,13,20 However, presently the molecular mechanisms underlying ASCC3 nucleic acid translocase/helicase activities and its regulation are poorly understood.Here, we nd a hitherto unobserved mechanism of nucleic acid translocation/unwinding in ASCC3 and reveal that it is regulated by ASC1. Using cryogenic electron microscopy (cryoEM)/single-particle ...

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“…ALKBH5 functions with FTO to ensure balanced m6A modifications in the transcriptome ( Chen et al, 2021a ; Purslow et al, 2021 ; Wu et al, 2021 ). ALKBH3 was identified as another m6A demethylase with easier binding to tRNA m6A sites than mRNA or rRNA sites ( Esteve-Puig et al, 2021 ; Wollen et al, 2021 ). FTO expression is increased in breast cancer and promotes cell growth and metastasis ( Niu et al, 2019 ).…”

Section: M6a Roles and Disease Mechanismsmentioning

confidence: 99%

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

Liu

2022

Front. Genet.

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N6-methyladenosine (m6A) is a dynamic, reversible post-transcriptional modification, and the most common internal modification of eukaryotic messenger RNA (mRNA). Considerable evidence now shows that m6A alters gene expression, thereby regulating cell self-renewal, differentiation, invasion, and apoptotic processes. M6A methylation disorders are directly related to abnormal RNA metabolism, which may lead to tumor formation. M6A methyltransferase is the dominant catalyst during m6A modification; it removes m6A demethylase, promotes recognition by m6A binding proteins, and regulates mRNA metabolic processes. Bladder cancer (BC) is a urinary system malignant tumor, with complex etiology and high incidence rates. A well-differentiated or moderately differentiated pathological type at initial diagnosis accounts for most patients with BC. For differentiated superficial bladder urothelial carcinoma, the prognosis is normally good after surgery. However, due to poor epithelial cell differentiation, BC urothelial cell proliferation and infiltration may lead to invasive or metastatic BC, which lowers the 5-years survival rate and significantly affects clinical treatments in elderly patients. Here, we review the latest progress in m6A RNA methylation research and investigate its regulation on BC occurrence and development.

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ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA

Cited by 16 publications

References 103 publications

Construction and Validation of a m7G-Related Gene-Based Prognostic Model for Gastric Cancer

Construction and Validation of a m7G-Related Gene-Based Prognostic Model for Gastric Cancer

Extended DNA threading through a dual-engine motor module in the activating signal co-integrator complex

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

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