Pat1 activates late steps in mRNA decay by multiple mechanisms

Lobel, Joseph H.; Tibble, Ryan W.; Gross, John D.

doi:10.1101/594168

Cited by 7 publications

(25 citation statements)

References 46 publications

(57 reference statements)

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“…Since S. pombe Lsm1-7 has been observed to bind to oligoU RNAs as well as oligoA RNAs in the presence of Pat1 (Lobel et al 2019), we first analyzed binding to four 15mers: U15, U14A, U13AA, and A15 under stringent binding conditions including 0.1 mg/mL competitor tRNA, 0.1 mg/mL sodium heparin and 0.1 mg/mL BSA. We find that U15, U14A and U13AA all bind tightly to Lsm1-7; in contrast, A15 does not bind in our assay (Figure 3c).…”

Section: Rna Binding Properties Of the Lsm1-7 Complexmentioning

confidence: 99%

“…The Lsm1-7 complex is cytoplasmic and mediates messenger-RNA (mRNA) decay, a major post-transcriptional mechanism for regulating gene expression (Bouveret et al 2000;Tharun et al 2000;Moore 2005;Parker 2012). Binding of the Lsm1-7 complex to mRNA is a key event in the decay pathway as it also binds the protein Pat1 (Chowdhury et al 2007;Sharif and Conti 2013;Lobel et al 2019). Pat1 then recruits a complex consisting of the decapping enzyme Dcp2 and its activators Dcp1, Edc1 and Edc2 (Mugridge et al 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to activating mRNA decapping, Lsm1-7 has many other functions including formation of phase-separated processing bodies (P-bodies) (Decker et al 2007;Reijns et al 2008), protecting 3′ ends of mRNA from 3′-5′ degradation by the exosome (He and Parker 2001;Tharun et al 2005), stabilizing specific RNAs during starvation and autophagy (Gatica et al 2019), suppressing translation of stress-activated RNAs during osmotic shock (Garre et al 2018), and promoting translation of viral RNAs (Jungfleisch et al 2015). Human and S. pombe Lsm1-7 complexes bind tightly to oligouridylate (hereafter, oligoU) RNAs (Lyons et al 2014; Cold Spring Harbor Laboratory Press on October 31, 2020 -Published by rnajournal.cshlp.org Downloaded from Lobel et al 2019). In contrast, the Lsm1-7-Pat1 complex binds tightly to oligoadenylate (hereafter, oligoA) RNAs (Chowdhury et al 2007;Chowdhury et al 2014;Lobel et al 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Human and S. pombe Lsm1-7 complexes bind tightly to oligouridylate (hereafter, oligoU) RNAs (Lyons et al 2014; Cold Spring Harbor Laboratory Press on October 31, 2020 -Published by rnajournal.cshlp.org Downloaded from Lobel et al 2019). In contrast, the Lsm1-7-Pat1 complex binds tightly to oligoadenylate (hereafter, oligoA) RNAs (Chowdhury et al 2007;Chowdhury et al 2014;Lobel et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis for the distinct cellular functions of the Lsm1–7 and Lsm2–8 complexes

Eric

Virta

Hayes

et al. 2020

RNA

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Eukaryotes possess eight highly conserved Lsm (like Sm) proteins that assemble into circular, heteroheptameric complexes, bind RNA, and direct a diverse range of biological processes. Among the many essential functions of Lsm proteins, the cytoplasmic Lsm1-7 complex initiates mRNA decay, while the nuclear Lsm2-8 complex acts as a chaperone for U6 spliceosomal RNA. It has been unclear how these complexes perform their distinct functions while differing by only one out of seven subunits. Here, we elucidate the molecular basis for Lsm-RNA recognition and present four high-resolution structures of Lsm complexes bound to RNAs. The structures of Lsm2-8 bound to RNA identify the unique 2′,3′ cyclic phosphate end of U6 as a prime determinant of specificity. In contrast, the Lsm1-7 complex strongly discriminates against cyclic phosphates and tightly binds to oligouridylate tracts with terminal purines. Lsm5 uniquely recognizes purine bases, explaining its divergent sequence relative to other Lsm subunits. Lsm1-7 loads onto RNA from the 3′ end and removal of the Lsm1 C-terminal region allows Lsm1-7 to scan along RNA, suggesting a gated mechanism for accessing internal binding sites. These data reveal the molecular basis for RNA binding by Lsm proteins, a fundamental step in the formation of molecular assemblies that are central to eukaryotic mRNA metabolism.

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Section: Rna Binding Properties Of the Lsm1-7 Complexmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular basis for the distinct cellular functions of the Lsm1–7 and Lsm2–8 complexes

Eric

Virta

Hayes

et al. 2020

RNA

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“…In HeLa and cardiomyocytic HL‐1 cells, crosslinks were identified in two neighboring peptides in the Pat1 Mid domain, as well as a peptide corresponding to the basic patch in PatC (Liao et al ; Castello et al ). The Mid domain thus binds RNA directly and may also participate in stable interaction with the PatC domain and the Lsm1‐7 complex (Braun et al ; Lobel et al ).…”

Section: Introductionmentioning

confidence: 99%

Pat1 RNA‐binding proteins: Multitasking shuttling proteins

2019

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Post-transcriptional regulation of gene expression is largely achieved at the level of splicing in the nucleus, and translation and mRNA decay in the cytosol. While the regulation may be global, through the direct inhibition of central factors, such as the spliceosome, translation initiation factors and mRNA decay enzymes, in many instances transcripts bearing specific sequences or particular features are regulated by RNA-binding factors which mobilize or impede recruitment of these machineries. This review focuses on the Pat1 family of RNA-binding proteins, conserved from yeast to man, that enhance the removal of the 5 0 cap by the decapping enzyme Dcp1/2, leading to mRNA decay and also have roles in translational repression. Like Dcp1/2, other decapping coactivators, including DDX6 and Edc3, and translational repressor proteins, Pat1 proteins are enriched in cytoplasmic P-bodies, which have a principal role in mRNA storage. They also concentrate in nuclear Cajalbodies and splicing speckles and in man, impact splice site choice in some pre-mRNAs. Pivotal to these functions is the association of Pat1 proteins with distinct heptameric Lsm complexes: the cytosolic Pat1/Lsm1-7 complex mediates mRNA decay and the nuclear Pat1/Lsm2-8 complex alternative splicing. This dual role of human Pat1b illustrates the power of paralogous complexes to impact distinct processes in separate compartments. The review highlights our recent findings that Pat1b mediates the decay of AU-rich mRNAs, which are particularly enriched in P-bodies, unlike the decapping activator DDX6, which acts on GC-rich mRNAs, that tend to be excluded from P-bodies, and discuss the implications for mRNA decay pathways. This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability RNRNA Processing > Splicing Regulation/Alternative Splicing Translation > Translation Regulation K E Y W O R D S3 0 -5 0 decay, 5 0 -3 0 decay, alternative splicing, deadenylation, RNA processing

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Dcp2 C-terminal Cis-Binding Elements Control Selective Targeting of the Decapping Enzyme by Forming Distinct Decapping Complexes

Jacobson

2021

Preprint

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A single Dcp1-Dcp2 decapping enzyme targets diverse classes of yeast mRNAs for decapping-dependent 5′ to 3′ decay, but the molecular mechanisms controlling selective mRNA targeting by the enzyme remain elusive. Through extensive genetic analyses we uncover cis-regulatory elements in the Dcp2 C-terminal domain that control selective targeting of the decapping enzyme by forming distinct decapping complexes. Two Upf1-binding motifs target the decapping enzyme to NMD substrates, and a single Edc3-binding motif targets both Edc3 and Dhh1 substrates. Pat1-binding leucine-rich motifs target Edc3 and Dhh1 substrates under selective conditions. Although it functions as a unique targeting component of specific complexes, Edc3 is a common component of multiple complexes. Xrn1 also has a specific Dcp2 binding site, allowing it to be directly recruited to decapping complexes. Collectively, our results demonstrate that Upf1, Edc3, and Pat1 function as regulatory subunits of the holo-decapping enzyme, controlling both its targeting specificity and enzymatic activation.

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Pat1 activates late steps in mRNA decay by multiple mechanisms

Cited by 7 publications

References 46 publications

Molecular basis for the distinct cellular functions of the Lsm1–7 and Lsm2–8 complexes

Molecular basis for the distinct cellular functions of the Lsm1–7 and Lsm2–8 complexes

Pat1 RNA‐binding proteins: Multitasking shuttling proteins

Dcp2 C-terminal Cis-Binding Elements Control Selective Targeting of the Decapping Enzyme by Forming Distinct Decapping Complexes

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