DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs

Li, Manqing; Kao, Elaine; Malone, Dane; Gao, Xia; Wang, Jean Y. J.; David, Michael

doi:10.1038/s41594-018-0142-5

Cited by 94 publications

(135 citation statements)

References 28 publications

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“…This aspartate is near a histidine in NONU-1 and forms the conserved DxH motif. More distant branches of the IF3-C fold include domains that bind, cleave, or process RNA, including the RNAseG/E nucleases (Fukui et al 2008), the synaptojanin/calcineurin domain phosphoesterases and nucleases , the Schlafen domain endoribonucleases (Makarova et al 2001;Li et al 2018;Yang et al 2018), and the RtcA RNA end cyclases ( Figure S3B, (Palm et al 2000)).…”

Section: Evolution Of Nonu-1 and Smr-domain Proteinsmentioning

confidence: 99%

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

Glover

Burroughs

Egelhofer

et al. 2019

Preprint

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Cellular translation surveillance rescues ribosomes that stall on problematic mRNAs. During translation surveillance, endonucleolytic cleavage of the problematic mRNA is a critical step in rescuing stalled ribosomes. However, the nuclease(s) responsible remain unknown. Here we identify NONU-1 as a novel endoribonuclease required for translation surveillance pathways including No-Go and Nonstop mRNA Decay. We show that: (1) NONU-1 reduces Nonstop and No-Go mRNA levels; (2) NONU-1 contains an Smr RNase domain required for mRNA decay and with properties similar to the unknown endonuclease; and (3) the domain architecture and catalytic residues of NONU-1 are conserved throughout metazoans and eukaryotes, respectively. We extend our results in C. elegans to homologous factors in S. cerevisiae, showing conservation of function of the NONU-1 protein across billions of years of evolution.Our work establishes the identity of a previously unknown factor critical to translation surveillance and will inform mechanistic studies at the intersection of translation and mRNA decay. 1 5 10 15 20 25 2 30 35 40 45 50 that organism. NONU-1 contains a conserved IF3-C fold domain previously implicated in processing RNA. Our results identify a critical new component of the translation surveillance machinery in two model organisms and suggest why this factor has been recalcitrant to discovery in S. cerevisiae. RESULTS nonu-1 encodes a novel factor required for Nonstop mRNA DecayWe previously developed a phenotypic reporter in C. elegans that allowed us to identify Nonstop mRNA Decay factors via reverse and forward genetics ( Figure 1A, (Arribere and Fire 2018)).Briefly, the reporter was constructed using the unc-54 locus as expression and function of this gene has been extensively studied (Brenner 1974;Epstein et al. 1974;Dibb et al. 1985Dibb et al. , 1989Moerman et al. 1982;Bejsovec and Anderson 1988;Anderson and Brenner 1984) and unc-54 has been used in previous suppressor screens (Hodgkin et al. 1989). To construct a Nonstop reporter at the unc-54 locus we first integrated a GFP at the C-terminus of UNC-54 by CRISPR/Cas9. We also removed all stop codons from the 3'UTR and integrated a ribosomal skipping T2A sequence between the C-terminal GFP and the remainder of the 3'UTR. The T2A sequence is a viral-derived peptide that cotranslationally releases the upstream protein and allows UNC-54::GFP to escape Nonstop protein decay (so-called "Ribosome Quality Control", (Bengtson and Joazeiro 2010;Shao et al. 2013;Shen et al. 2015)). We hereafter refer to the unc-54::gfp::t2a::nonstop reporter as unc-54 (Nonstop). Animals with the unc-54 (Nonstop) reporter deficient in Nonstop mRNA Decay exhibit derepression of the locus, as evidenced by increased GFP fluorescence, mRNA expression, and egg laying (unc-54 encodes a muscle myosin required in the vulva for egg laying) ( Figure 1B, (Arribere and Fire 2018)).Although our initial screen successfully identified C. elegans' skih-2 and ttc-37 (homologs of S. cerevisiae SKI2 and SKI3, respectively), ...

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Section: Evolution Of Nonu-1 and Smr-domain Proteinsmentioning

confidence: 99%

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

Glover

Burroughs

Egelhofer

et al. 2019

Preprint

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“…This selective effect of WNV on only a subset of tRNAs highlights their differential susceptibility to these virally exploited regulatory mechanisms. In support of this view, enzymes catalyzing tRNA posttranscriptional modifications, processing, and degradation, which importantly impact tRNA abundance, exhibit tRNA preferences (25,(31)(32)(33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 89%

“…We speculate that Slfn11-mediated, WNV infection-triggered degradation of these four tRNAs requires levels of Slfn11 higher than those found in A172-SCR cells. In support of this interpretation, it has been reported that transient overexpression of Slfn11 preferentially degrades a subset of tRNAs (25), potentially impairing protein expression from cotransfected plasmids in an unspecific manner (3). Nevertheless, WNV replicated similarly in A172-SCR and -BC cells, indicating that changes in the abundances of these four tRNAs did not impact WNV replication.…”

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confidence: 92%

Schlafen 11 Restricts Flavivirus Replication

Valdez

Salvador

Palermo

et al. 2019

J Virol

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Schlafen 11 (Slfn11) is an interferon-stimulated gene that controls the synthesis of proteins by regulating tRNA abundance. Likely through this mechanism, Slfn11 has previously been shown to impair human immunodeficiency virus type 1 (HIV-1) infection and the expression of codon-biased open reading frames. Because replication of positive-sense single-stranded RNA [(ϩ)ssRNA] viruses requires the immediate translation of the incoming viral genome, whereas negative-sense singlestranded RNA [(Ϫ)ssRNA] viruses carry at infection an RNA replicase that makes multiple translation-competent copies of the incoming viral genome, we reasoned that (ϩ)ssRNA viruses will be more sensitive to the effect of Slfn11 on protein synthesis than (Ϫ)ssRNA viruses. To evaluate this hypothesis, we tested the effects of Slfn11 on the replication of a panel of ssRNA viruses in the human glioblastoma cell line A172, which naturally expresses Slfn11. Depletion of Slfn11 significantly increased the replication of (ϩ)ssRNA viruses from the Flavivirus genus, including West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV), but had no significant effect on the replication of the (Ϫ)ssRNA viruses vesicular stomatitis virus (VSV) (Rhabdoviridae family) and Rift Valley fever virus (RVFV) (Phenuiviridae family). Quantification of the ratio of genome-containing viral particles to PFU indicated that Slfn11 impairs WNV infectivity. Intriguingly, Slfn11 prevented WNV-induced downregulation of a subset of tRNAs implicated in the translation of 11.8% of the viral polyprotein. Lowabundance tRNAs might promote optimal protein folding and enhance viral infectivity, as previously reported. In summary, this study demonstrates that Slfn11 restricts flavivirus replication by impairing viral infectivity. IMPORTANCE We provide evidence that the cellular protein Schlafen 11 (Slfn11) impairs replication of flaviviruses, including West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV). However, replication of single-stranded negative RNA viruses was not affected. Specifically, Slfn11 decreases the infectivity of WNV potentially by preventing virus-induced modifications of the host tRNA repertoire that could lead to enhanced viral protein folding. Furthermore, we demonstrate that Slfn11 is not the limiting factor of this novel broad antiviral pathway. KEYWORDS Schlafen 11, virus restriction factors, flavivirusS uccessful viral replication depends on the ability of the virus to appropriate the host translational machinery. The innate immune response exploits this dependency to control viral replication. Many interferon (IFN)-stimulated genes (ISGs) that regulate protein translation are well known to restrict virus replication, including protein kinase R, the interferon-induced proteins with tetratricopeptide repeats family of proteins, zinc finger antiviral protein, and the 2=,5=-oligoadenylate/RNase L pathway. The Schlafen (Slfn) proteins, another family of ISGs, were first identified as being important regulators of T cell differentiation and gr...

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“…While mouse Slfns have been reported to function in immune response and lymphocyte development, functions of human SLFNs have not been well studied until recently [2][3][4]. SLFN11, a putative DNA/RNA helicase, has lately been analyzed from multiple aspects such as DNA damage response [5,6], RNA cleavage [7], and defense of viral infection [8][9][10]. As for the role in DNA damage response, accumulative studies have shown that SLFN11 augments sensitivity to a wide range of DNA-damaging agents such as platinum-derivatives, topoisomerase inhibitors, PARP inhibitors and replication inhibitors [4][5][6][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development

Moribe¹,

Nishikori²,

Sasanuma

et al. 2020

Preprint

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Background SLFN11 enhances cellular toxicity of genotoxic anti-cancer agents, and its important role under physiological conditions has not been appreciated yet. Somatic hypermutations and class switch recombination that can cause physiological genotoxic stress arise in germinal center B cells (GCBs). GCBs are a major origin of B-cell lymphomas that are frequently treated by cytosine arabinoside, a genotoxic anti-cancer agent. Objective To clarify the expression profile of SLFN11 in different stages of B cells and B-cell lymphomas. Methods We analyzed the expression of SLFN11 by mining publicly available databases for different stages of normal B cells and various types of B-cell lymphoma lines and also by performing immunohistochemical staining of human lymph nodes. We investigated the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in B-cell lymphoma lines and examined the therapeutic efficacy of these epigenetic modifiers in the combination with cytosine arabinoside. Results SLFN11 expression was specifically low in GCBs compared to non-GCBs, which was consolidated by the immunohistochemical staining for SLFN11 with human lymph nodes. SLFN11 expression levels in B-cell lymphoma lines largely correlated to those of their normal counterparts. The epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphomas and made the lymphomas further susceptible to cytosine arabinoside. Conclusions The expression of SLFN11 may be epigenetically suppressed in GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.

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DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs

Cited by 94 publications

References 28 publications

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

Schlafen 11 Restricts Flavivirus Replication

Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development

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