Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

Dubiez, Etienne; Pellegrini, Erika; Finderup Brask, Maja; Garland, William; Foucher, Anne-Emmanuelle; Huard, Karine; Heick Jensen, Torben; Cusack, Stephen; Kadlec, Jan

doi:10.1016/j.celrep.2023.113639

Cited by 3 publications

(2 citation statements)

References 68 publications

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“…In an alternative, but not mutually exclusive, scenario the nuclear history of these transcripts might impact the involved cytoplasmic processes. In the absence of active NEXT-targeting, the competing process of PHAX-mediated nuclear export prevails 37,70 , possibly enabling the resident RNA to be subjected to cytoplasmic 3’end modification as is the case for the conventional UsnRNA PHAX-export substrates 94,95 . However, different from the productive 3’end processing and RNP assembly of snRNA prior to their nuclear re-import, excess NEXT substrates are tailed and subjected to removal.…”

Section: Discussionmentioning

confidence: 99%

“…Substrate access is facilitated by the exosome-associated RNA helicase MTR4 27–29 , which connects to one of two primary nucleoplasmic adaptors: the nuclear exosome targeting (NEXT) complex 30 or the polyA (pA) tail exosome targeting (PAXT) connection 31,32 . NEXT forms a dimer of MTR4-ZCCHC8-RBM7 heterotrimers 33,34 and can target the exosome to short, TSS-proximal, pA - transcripts via its connection to the 5’cap-binding complex (CBC) 35–37 . Conversely, PAXT consists of a core MTR4-ZFC3H1 heterodimer, that associates with the nuclear pA binding protein (PABPN1) to facilitate the exosome-mediated decay of a variety of pA + RNAs 31,32,38–40 .…”

Section: Introductionmentioning

confidence: 99%

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RNA 3’end tailing safeguards cells against products of pervasive transcription termination

Wu,

Rouvière,

Schmid

et al. 2024

Preprint

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Premature transcription termination yields a wealth of unadenylated (pA-) RNA. Although this can be targeted for degradation by the Nuclear EXosome Targeting (NEXT) complex, possible back-up pathways remain poorly understood. Here, we find RNA 3′ end uridylation and adenylation upon NEXT inactivation. U-tailed RNAs are generally short and modified by the cytoplasmic tailing enzymes, TUT4/7, following their PHAX-dependent nuclear export and prior to their degradation by the cytoplasmic exosome or the exoribonuclease DIS3L2. Longer RNAs are instead adenylated redundantly by enzymes TENT2, PAPOLA and PAPOLG. These transcripts are either degraded via the nuclear Poly(A) tail eXosome Targeting (PAXT) connection or exported by conventional factors and removed by the cytoplasmic exosome in a translation-dependent manner. Failure to do so decreases global translation and induces cell death. We conclude that post-transcriptional 3′ end modification and removal of excess pA- RNA is achieved by tailing enzymes and export factors shared with productive RNA pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RNA 3’end tailing safeguards cells against products of pervasive transcription termination

Wu,

Rouvière,

Schmid

et al. 2024

Preprint

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Nuclear mRNA decay: regulatory networks that control gene expression

Rambout,

Maquat

2024

Nat Rev Genet

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Structural basis of Spliced Leader RNA recognition by theTrypanosoma bruceicap-binding complex

Bernhard,

Petržílková,

Popelářová

et al. 2024

Preprint

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Kinetoplastids are a clade of eukaryotic protozoans that include human parasitic pathogens like trypanosomes and Leishmania species. In these organisms, protein-coding genes are transcribed as polycistronic pre-mRNAs, which need to be processed by the coupled action of trans-splicing and polyadenylation to yield monogenic mature mRNAs. During trans-splicing, a universal RNA sequence, the spliced leader RNA (SL RNA) mini-exon, is added to the 5'-end of each mRNA. The 5'-end of this mini-exon carries a hypermethylated cap structure and is bound by a trypanosomatid-specific cap-binding complex (CBC). The function of three of the kinetoplastid CBC subunits is unknown, but an essential role in cap binding and trans-splicing has been suggested. Here, we report cryo-EM structures that reveal the molecular architecture of the Trypanosoma brucei CBC (TbCBC) complex. We find that TbCBC interacts with two distinct features of the SL RNA. The TbCBP20 subunit interacts with the m7G cap while TbCBP66 recognizes double-stranded portions of the SL RNA. Our findings pave the way for future research on mRNA maturation in kinetoplasts. Moreover, the observed similarities and differences between TbCBC and the human cap-binding complex will be crucial for considering the potential of TbCBC as a target for anti-trypanosomatid drug development.

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Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

Cited by 3 publications

References 68 publications

RNA 3’end tailing safeguards cells against products of pervasive transcription termination

RNA 3’end tailing safeguards cells against products of pervasive transcription termination

Nuclear mRNA decay: regulatory networks that control gene expression

Structural basis of Spliced Leader RNA recognition by theTrypanosoma bruceicap-binding complex

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